Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+].CB(O)O>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 910.3 %

Procedure:
To a mixture of 4-(5-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.33 g), palladium (II) acetate (175 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (639 mg), potassium fluoride (5.43 g) and methylboronic acid (2.80 g) was added tetrahydrofuran (120 mL), and the mixture was refluxed under a nitrogen stream for 3 hr. To the reaction mixture were added ethyl acetate and saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (3.93 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]([C:26]#[C:27][Si](C)(C)C)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CO>[C:26]([C:25]1[C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:11]([C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[O:12])=[CH:18][CH:17]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)#[CH:27]
Reactant: Cn1c(C(=O)c2ccc(Oc3ncccc3C#C[Si](C)(C)C)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccnc1Oc1ccc(C(=O)c2nc3ccccc3n2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1-M ethyl-1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trimethylsilyl)ethynyl)pyridin-2-yloxy)phenyl)methanone (0.19 g, 0.44 mmol) and potassium carbonate (0.12 g, 0.88 mmol) was suspended in 1 mL MeOH. The mixture was stirred for 2 h at RT. Purification by prep-plate TLC (10% MeOH/DCM) afforded (4-(3-ethynylpyridin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone. MS (ESI, pos. ion) m/z: 354.0 (M+1). IC50 (uM) +++.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:27]=[C:26]([C:28]([O:30]CC)=[O:29])[NH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[NH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)n[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)n[nH]1
Yield: 9.3 %

Procedure:
A solution of ethyl 3-(2,4-dibenzyloxyphenyl)-pyrazole-5-carboxylate (1.5 g) in methanol (20 mL) and THF(10 mL) is treated with aqueous 10% KOH (7.5 mL) and refluxed for 2 hours. The solution is evaporated, brought to pH 1 with 1 M HCl, and the precipitate filtered. The solid is purified by flash chromatography on silica, eluting with dichloromethane/methanol (98:2). Fractions homogeneous in the required product are combined and evaporated. The residue is recrystallized from ethyl acetate to give 3-(2,4-dibenzyloxyphenyl)-pyrazole-5-carboxylic acid as colourless crystals (0.13 g), m.p. 218-219° C. 1H NMR (CDCl3) 5.1 (2H,s), 5.2(2H,s), 6.68(1H,d), 6.72(1H,s), 7.3-7.5(11H,m), 7.7(1H,d).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:3]=1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: Cc1cc(N2CCC3(CC2)OCCO3)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(N2CCC(=O)CC2)ncn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 8-(6-methylpyrimidin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4.64 g, 19.7 mmol) in acetone (45 mL) was added 2 N HCl (180 g, 150 mL, 4.94 mol) and stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, then adjusted to pH 7 with NaHCO3 solution. The aqueous phase was extracted 4 times with CH2Cl2, the organic layers were combined, dried over Na2SO4 and the solvent was evaporated. The title compound was obtained as light brown liquid (2.7 g, 72%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[C:35]#[N:36])=[CH:22][C:21]2=[O:37])[C:17]([OH:19])=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:38][C:39]1[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][CH:40]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH:16]([N:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[C:35]#[N:36])=[CH:22][C:21]2=[O:37])[C:17]([NH:38][C:39]2[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])=[CH:41][CH:40]=2)=[O:19])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2CCC(O[Si](C)(C)C(C)(C)C)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC2CCC(O[Si](C)(C)C(C)(C)C)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
400 mg (734 μmol) of 3-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (mixture of two racemic diastereomers), 142 mg (734 μmol) of tert-butyl 4-aminobenzoate, 104 mg (734 μmol) of Oxima and 114 μl (734 μmol) of DIC in 7.3 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (40 g cartridge, 40 ml/min, cyclohexane/ethyl acetate gradient). Yield: 341 mg (64% of theory)
Reaction SMILES: C(OC([NH:8][C@H:9]([C:19]([NH:21][C@H:22]([C:24]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:41]([C:42]#[N:43])=[C:40]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[N:39]=[C:38]([S:49][CH2:50][C:51]3[N:52]=[C:53]([C:56]4[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=4)[S:54][CH:55]=3)[C:37]=2[C:63]#[N:64])=[CH:32][CH:31]=1)=[O:25])[CH3:23])=[O:20])[CH2:10][NH:11]C(OC(C)(C)C)=O)=O)(C)(C)C.Cl.[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69]>ClCCl.C(OCC)C>[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69].[F:66][C:67]([F:72])([F:71])[C:68]([OH:70])=[O:69].[NH2:11][CH2:10][C@@H:9]([C:19]([NH:21][C@H:22]([C:24]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[C:41]([C:42]#[N:43])=[C:40]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[N:39]=[C:38]([S:49][CH2:50][C:51]3[N:52]=[C:53]([C:56]4[CH:57]=[CH:58][C:59]([Cl:62])=[CH:60][CH:61]=4)[S:54][CH:55]=3)[C:37]=2[C:63]#[N:64])=[CH:34][CH:35]=1)=[O:25])[CH3:23])=[O:20])[NH2:8]
Reactant: C[C@H](NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@@H](N)CN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 6 h

Procedure:
290 mg (0.311 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)amino)-L-alanyl-L-alaninate were dissolved in 5 ml dichloromethane, and 3.113 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 6 hours of stirring, a further 3.113 ml of a 1N solution of hydrogen chloride in diethyl ether were added and the mixture was stirred at room temperature overnight. Another 10 ml of a 1N solution of hydrogen chloride in diethyl ether were added, and stirring at room temperature was continued for a further 24 hours. The precipitated solid was then filtered off with suction, washed with diethyl ether and dried under reduced pressure. The crude product was dissolved in 2 ml of dichloromethane, and 0.126 ml (1.632 mmol) of trifluoroacetic acid was added. After 6 hours of stirring, the reaction mixture was concentrated and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). 81 mg (27% of theory) of the target compound were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C=C.[Na].C(OCC)(=O)C.[CH2:24]([OH:27])[CH2:25][OH:26]>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[O:26][CH2:25][CH2:24][OH:27]
Reactant: OCCO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: C=C
Agent: [Na]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(OCCO)cc1Cl
Temperature: 25 °C

Procedure:
94.8 g (0.40 moles) 1,5-dichloro-2,4-dinitrobenzene in 580 ml ethylene glycol is heated to 50° C. To the mixture is then very gradually added, with stirring, 50.4 g (0.60 moles) sodium ethylene glycoxide over approximately 6 hours. One hour after addition is complete, TLC (ethyl acetate) shows the reaction is complete. The heat is turned off and the mixture is allowed to cool to room temperature. The precipitated product is collected by vacuum filtration and is washed with water. The water causes additional product to precipitate in the filtrate. The product is dried in a vacuum oven at 50° C. Yield of the combined crops is 82.7 g (78.8%), m.p. 98°-100° C.
Reaction SMILES: C([C:4]1[C:5](=[O:16])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10](Cl)=[C:9](O)[CH:8]=2)(O)=O.C([N:20](C(C)C)CC)(C)C.ClCOCC1C=CC=CC=1.CN(C)CCN>C1COCC1.CN(C=O)C>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([NH2:20])[C:5]1=[O:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2cc(Cl)c(O)cc2oc1=O
Agent: CN(C)CCN
Agent: ClCOCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1cc2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117.9 %

Procedure:
241 mg 3-carboxy-6-chloro-7-hydroxy coumarin (1 mmol) dissolved in the mixture of 5 ml THF and 5 ml DMF was added 200 ul diisopropylethylamine (DIEA, 1.1 mmol) and 330 mg O-(N-succinium)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate (TSTU, 1.1 mmol). After stirring at room temperature for 20 minutes under nitrogen atmosphere, the reaction mixture was added 400 ul of DIEA and 460 ul benzyl chloromethyl ether (BOM-Cl) and stirred for another 2 hours at room temperature. The resulted mixture was then pulled high vacuum for 2 hours and 1 ml THF, 480 ul 2-dimethyaminoethylamine was added into the solution afterwards. After the reaction mixture was allowed to react at room temperature for 1 hour, the crude product was pulled high vacuum again overnight and purified on a silica gel column (chloroform: methanol=95:5 as eluent). 190 mg colorless solid was obtained as product, 44% yield. 1H NMR (CDCl3, ppm): 2.32 (d, 6H), 2.56 (t, 2H), 2.16 (t, 2H), 4.76 (s, 2H), 5.46 (s, 2H), 7.33 (m, 7H), 7.68 (s, 1H), 8.76 (s, 1H). MS: C22H23O5N2Cl, 430.3 calculated; 431.2 (M+1) found.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([Br:7])[CH:4]=[N:3]1.[N:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[Br:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:15])[CH:6]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1cc(Br)cn1
Product: O=C(On1cc(Br)cn1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-4-bromopyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (85%, crystals).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[H][H]>CO.[Pd]>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:11]#[N:12])=[N:4][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1C#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cnc1C#N
Yield: 92.8 %

Procedure:
A mixture of 3-methyl-5-nitropicolinonitrile (2.9 g, 17.8 mmol) and Pd/C (cat.) in MeOH (60 mL) was hydrogenated overnight with a balloon of hydrogen. Pd/C was removed through a pad of celite and the filtrate was evaporated to dryness to afford 2.2 g of 5-amino-3-methylpicolinonitrile as a greenish solid. 1H NMR (300 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.79 (s, 1H), 6.32 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]([CH3:17])[CH3:16])[C:4]=2[N:3]=1.[C:18]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:18])[C:7](=[O:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]([CH3:16])[CH3:17])[C:4]=2[N:3]=1
Reactant: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C(C)C
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Yield: 84.6 %

Procedure:
The crude compound (7R)-2-chloro-7-ethyl-8-isopropyl-5,7-dihydropteridin-6-one 22c (12.10 g, 47.50 mmol) was dissolved in 180 mL of acetone followed by the addition of methyl p-toluenesulfonate (13.28 g, 71.30 mmol) and potassium carbonate (13.11 g, 95 mmol). The reaction solution was heated to reflux for 3 hours with stirring and filtered. The filtrate was concentrated under reduced pressure, added with 100 mL of water and extracted with dichloromethane (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (100 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one 22d (10.80 g, yield: 84.7%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:22][O:23][CH2:24][CH3:25])[CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN.O>C(O)C>[CH2:24]([O:23][N:22]=[C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:10][NH2:11])[CH3:25]
Reactant: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCON=C(CN)c1ncc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To 3.00 g of N-[2-(3,5-dichloropyridin-2-yl)-2-(ethoxyimino)ethyl]phthalimide in 30 ml of ethanol, 793 mg of hydrazine monohydrate was added, and the mixture was stirred at 70° C. for 3 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 100 ml of water and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.62 g of the desired crude product as a brown oil. The oil was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[NH:21]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=4)=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][N:19]=[N:20]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Yield: 48 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3-trifluoromethylphenylboronic acid (11 mg, 0.06 mmol). The title compound was obtained in 48% yield (10.8 mg). MS (ESI+) calcd mass for C18H12F3N5O2S2 451.038451, found 451.038591.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:7]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[P:8](=[O:11])([OH:10])[OH:9])(=[O:6])[OH:5])[CH3:2].[CH3:19][Mg]Br>O1CCCC1>[CH2:1]([O:3][P:4]([CH:7]([N:12]1[CH2:13][CH2:14][C:15]([OH:18])([CH3:19])[CH2:16][CH2:17]1)[P:8](=[O:9])([OH:10])[OH:11])(=[O:5])[OH:6])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCOP(=O)(O)C(N1CCC(=O)CC1)P(=O)(O)O
Solvent: C1CCOC1
Product: CCOP(=O)(O)C(N1CCC(C)(O)CC1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
43 g (0.11 mol) of 4-oxopiperidinomethylene bisphosphonic acid ethyl ester was dissolved in 500 mt of dried tetrahydrofuran, and 250 ml (0.25 mol) of a methyl magnesium bromide solution in tetrahydrofuran (concentration: 1 mol/) was added thereto. The mixture was stirred at 25° C. for 2 hours, then subjected to post treatment and purified by column chromatography (SiO2, cyclohexane/CHCl3 =1/1) to give 30.7 g (68.5%) of 4-hydroxy-4-methylpiperidinomethylene bisphosphonic acid ethyl ester as an oily substance. To 15.8 g (39.5 mmol) of this ester, 7.6 g (47.2 mmol) of diethylaminosulfur trifluoride was added at -78° C. in CH2Cl2, and the mixture was stirred at room temperature for 5 hours. The reaction solution was purified by column chromatography (SiO2, hexane/isopropylether=5/1) to give 6.3 (40%) of the above identified compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH2:17])([O-])=O>CCO.[Pd]>[F:15][C:13]([F:14])([F:16])[S:10]([C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:17])=[CH:6][CH:7]=1)(=[O:11])=[O:12]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1N

Procedure:
Dissolve 2-nitro-4-trifluoromethylsulfonyl-phenylamine (530 mg) in EtOH (50 mL) and hydrogenate over Pd/C (10%) for 6 hours. Filter the mixture and concentrate the filtrate in vacuo to obtain 4-trifluoromethylsulfonyl-benzene-1,2-diamine. E. 5-Trifluoromethylsulfonyl-1,3-dihydro-benzimidazol-2-one
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[CH2:5][CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[NH2:7].[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])(=[O:21])[CH3:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:18])[CH2:5][CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[NH:7][C:25](=[O:26])[CH:24]([CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)CC(N)c1ccc2ccccc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)C(CSC(C)=O)Cc1ccccc1)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
Mix equimolar parts of β-(2-naphthyl)-β-alanine methyl ester, hydrochloride and 2-acetylthiomethyl-3-phenylpropanoic acid with 1.2 equivalents each of EDC, triethylamine and HOBT in DMF and stir overnight. Evaporate the solvent, partition between EtOAc and water, and concentrate the organic layer. Separate on silica using ether/hexane and crystallize from acetone/hexane to obtain the title compound, m.p. 133°-135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([NH:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25])=[O:21])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[C@@H](N)CO
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 4 g (14.17 mmol) of 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 1.83 g (15.59 mmol) of (R)-(−)-2-aminohexanol and 7.166 g (70.85 mmol) of 4-methylmorpholine were suspended in 28 ml of dichloromethane. 5 g (15.59 mmol) of TBTU were then added, and the mixture was stirred at room temperature overnight. After 16 h, the mixture was diluted with 200 ml of dichloromethane and washed with 10% strength aqueous citric acid solution, with water and with saturated aqueous sodium chloride solution. The organic phase was concentrated and the residue obtained was purified on a silica gel cartridge (mobile phase dichloromethane:methanol=100:3). Concentration of the product fractions thus gave 3.83 g (71% of theory) of 8-(benzyloxy)-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:14]([CH3:36])=[CH:13][N:12]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([CH:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:15]2[C:14]([CH3:36])=[CH:13][N:12]=[C:11]([NH2:10])[CH:16]=2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: Cc1cnc(NC(=O)OC(C)(C)C)cc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cnc(N)cc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To an ethanol (5 ml) solution of t-butyl[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]carbamate (200 mg, 0.393 mmol) was added concentrated hydrochloric acid (6 ml). The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystallized from hexane:ethyl acetate to give the title compound (125 mg, 0.306 mmol, 78%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4](/[CH:5]=[C:6](\[Br:13])/[C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH3:18][C:19]1([CH3:33])[CH:21](/[CH:22]=[C:23](\[F:29])/[C:24](=[O:28])[O:25]CC)[CH:20]1[C:30]([O-:32])=[O:31]>>[CH3:17][C:2]1([CH3:1])[CH:4](/[CH:5]=[C:6](\[Br:13])/[C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH3:18][C:19]1([CH3:33])[CH:21](/[CH:22]=[C:23](\[F:29])/[C:24](=[O:25])[OH:28])[CH:20]1[C:30]([O-:32])=[O:31]
Reactant: CCOC(=O)/C(F)=C/C1C(C(=O)[O-])C1(C)C
Agent: CCCOC(=O)/C(Br)=C/C1C(C(=O)O)C1(C)C
Product: CC1(C)C(/C=C(\F)C(=O)O)C1C(=O)[O-]

Procedure:
Using the procedure of Step A of Example 14, (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(Z) -[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(Z)-[2-fluoro-3-oxo-3-hydroxy-propenyl]-cyclopropane-1-carboxylate which was reacted by the process of Step B of Example 14 to obtain (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(Z)-[2-fluoro-3-oxo-3-methoxypropenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+15.5°±2.5° (c=0.3% in chloroform).