Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][S:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:3])=[O:2].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][S:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][S:28]([C:20]1[O:19][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=1)(=[O:29])=[O:30])([O-:3])=[O:2]
Reactant: Nc1ccccc1SCc1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(CSc2ccccc2NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 41.4 %

Procedure:
Following General Procedure B, the title compound (520 mg, 41%) was prepared from 2-((3-nitrobenzyl)thio)aniline (741 mg, 2.85 mmol), benzofuran-2-sulfonyl chloride (616 mg, 2.85 mmol) in pyridine (10 ml).
Reaction SMILES: C(O)(C)C.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=O)[C:15](OC)=[O:16])=[CH:6]1.[BH4-].[Na+]>O>[OH:16][CH2:15][CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][CH:6]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OCCc1c[nH]c2ccccc12

Procedure:
A vigorously-stirred mixture of isopropanol (3 1), methyl 3- indolylglyoxylate (305 g) and sodium borohydride (125 g) was warmed to 40° - 50° and held at that temperature until the initial exothermic reaction was complete. The mixture was then heated to reflux for 4 hours, cooled and diluted with water (5 l). After acidification with hydrochloric acid the product was extracted into dichloromethane. The separated extract was washed with sodium carbonate solution to remove 3-indolylacetic acid and then with water. Evaporation of the solvent gave the crude product as a brown oil. This was distilled at 0.5 - 1 mm pressure (vapour temperature 160° - 190° ) and crystallised from toluene (1 l) to give the title compound as white to pale brown crystals m.p. 57° - 59°. Yield 170 g. (70% of theory).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[CH2:16])[CH:13]=2)[N:8]([CH3:17])[CH:7]=1)=[O:5])C>C(O)C.[C].[Pd]>[CH2:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:17])[CH:7]=[C:6]2[C:4]([OH:5])=[O:3])[CH3:16]
Reactant: C=Cc1ccc2c(c1)c(C(=O)OCC)cn2C
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc2c(c1)c(C(=O)O)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of 1-methyl-5-vinyl-1H-indole-3-carboxylic acid ethyl ester (934 mg) in ethanol (40 ml) was added 10% palladium carbon (containing about 50% water) (95 mg) at room temperature, and stirred at the same temperature for 4 hours under hydrogen gas flow. After completion of the reaction, the mixture was filtered through Celite, and then the filtrate was concentrated. The obtained residue was dissolved in ethanol (20 ml), 1N aqueous solution of sodium hydroxide (20 ml) was added thereto at room temperature, and stirred at 70° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then the solvent was evaporated. The obtained residue was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid aqueous solution, and the precipitated solid was collected by filtration to give the titled compound (797 mg) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([C:16]2[N:20]=[C:19](C(Cl)(Cl)Cl)[O:18][N:17]=2)[N:10]=1.Cl.[CH:32]1([CH2:35][O:36][CH2:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>CN(C=O)C>[CH:32]1([CH2:35][O:36][CH2:37][CH:38]2[CH2:43][CH2:42][N:41]([C:19]3[O:18][N:17]=[C:16]([C:11]4[N:10]=[C:9]([N:8]([CH3:7])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:14]=[C:13]([NH2:15])[N:12]=4)[N:20]=3)[CH2:40][CH2:39]2)[CH2:33][CH2:34]1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Reactant: C1CC(COCC2CC2)CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(COCC4CC4)CC3)n2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
Potassium carbonate (0.107 g, 0.776 mmol) and 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.150 g, 0.388 mmol) were added to a solution of 4-[(cyclopropylmethoxy)methyl]piperidine hydrochloride salt (Intermediate 198, 0.160 g, 0.776 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 h and then evaporated under vacuum to remove the DMF. The crude residue was dissolved in EtOAc (5 mL) and washed with water (3×3 mL). The aqueous washes were combined, re-extracted with EtOAc (2×3 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to provide a crude brown residue which was purified by preparative HPLC, Method B, to afford the title compound as an off-white solid (28 mg, 16%).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][OH:12]>>[S:1]([O:12][CH2:11][CH2:10][O:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[CH3:6])(=[O:4])(=[O:3])[NH2:2]
Reactant: Cc1ccccc1OCCO
Reactant: NS(=O)(=O)Cl
Product: Cc1ccccc1OCCOS(N)(=O)=O
Yield: 53 %

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-(2-methylphenoxy)ethanol in 53% yield as an off-white solid, mp 81.5°-83° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][OH:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30]I.O>O1CCCC1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][O:27][CH3:30])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCCC1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine (trans isomer) (0.30 g) was added to a stirred solution of tetrahydrofuran (2 ml) and sodium hydride (62.8%, 0.04 g) with ice-cooling. After 30 minutes, a solution of methyl iodide (0.14 g) in tetrahydrofuran (2 ml) was added to that stirred solution at 0° C. The reaction mixture was stirred for hours at room temperature, then poured into water (20 ml), extracted with chloroform (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpiperidine (trans isomer) (0.30 g) as an oil.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:39])=[C:11]([C:28]([NH:30][CH2:31][CH:32]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[OH:33])=[O:29])[C:12]([I:27])=[C:13]([C:25]=1[I:26])[C:14]([NH:16][CH2:17][CH:18]([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[OH:19])=[O:15])=[O:7])(=O)C.C(OCC(NC1C(I)=C(C(Cl)=O)C(I)=C(C=1I)C(Cl)=O)=O)(=O)C.C([O-])([O-])=O.[Na+].[Na+].OCCNCC(O)CO>CC(N(C)C)=O.CCOC(C)=O.C(Cl)Cl>[OH:24][CH:21]([CH2:22][OH:23])[CH2:20][CH:18]([OH:19])[CH2:17][NH:16][C:14](=[O:15])[C:13]1[C:25]([I:26])=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[C:10]([I:39])=[C:11]([C:28]([NH:30][CH2:31][CH:32]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[OH:33])=[O:29])[C:12]=1[I:27]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Agent: CC(=O)OCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Agent: O=C([O-])[O-]
Agent: OCCNCC(O)CO
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CO)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Yield: 86 %

Procedure:
5-Acetoxyacetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide. 69 g (0.1 g-mole) of 5-acetoxyacetamido-2,4,6-triiodoisophthaloyl chloride is dissolved in DMAc (140 ml) and anhydrous Na2CO3 (31.8 g, 0.3 g-mole) is added. To the solution, a DMAc solution (87 ml) containing 26.2 g (0.3 g-mole) of 3-(N-2-hydroxyethyl)amino-1,2-propanediol is added. The mixture is heated and stirred at 35°-40° C. until the reaction is completed as determined by the TLC analysis (EtOAc/CH2Cl2 ; 30/20). After the reaction, the inorganic salts are filtered and the filtrate containing the desired product is evaporated to dryness to give a gum. The gum is triturated with isopropyl alcohol to dissolve the excess amino-triol. The clear supernatant is decanted and the residual solid is dissolved in water (150 ml), treated with Amberlite® IR-120H resin and evaporated to dryness to give the desired product (77 g, 86% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[NH:6][C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl.C(Cl)Cl.CO>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[N:6]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc2[nH]c(C)nc2cc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(cc1Br)nc(C)n2COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a mixture of 5-bromo-6-methoxy-2-methyl-1H-benzo[d]imidazole (400 mg, 1.659 mmol) in DMF (3 mL) was added 60% wt NaH (80 mg, 1.991 mmol) at 0° C. The mixture was stirred from 0° C. to room temperature for 0.5 hours, then 2-trimethylsilylethyoxymethyl chloride (SEMCl, 0.352 mL, 1.991 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours then quenched with water and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (10-100% EtOAc/Heptane then 0-10% DCM/MeOH) to afford the title compound (310 mg, 50.3% yield) as an oil. MS (M+1)=373.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].BrC1C=NC([Cl:25])=C(C=1)C(O)=O.CN(C)C=O>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([Cl:25])=[O:8]
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: CON(C)C(=O)c1cc(Br)cnc1Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Br)cnc1Cl
Temperature: 80 °C

Procedure:
5-Bromo-2-chloro-N-methoxy-N-methylnicotinamide. To a mixture of 5-bromo-2-chloronicotinic acid (6 g, 25.5 mmol) in thionyl chloride (30 mL) was added a drop of N,N-dimethylformamide, and the reaction mixture was heated at 80° C. for 2 h. The mixture was cooled to room temperature, and concentrated to give crude 5-bromo-2-chloronicotinoyl chloride. A solution of O,N-dimethyl-hydroxylamine hydrochloride salt (3.45 g, 35.6 mmol) and triethylamine (7.48 g, 74.1 mmol) in dichloromethane (80 mL), and a solution of the above 5-bromo-2-chloronicotinoyl chloride in dichloromethane (20 mL) were added, and the reaction mixture was stirred overnight. The mixture was poured into water, and extracted with dichloromethane (50 mL×3). The combined organic layer was concentrated under reduced pressure, and purified on silica gel column (eluting with 5-10% ethyl acetate in petroleum ether) to give 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide as a solid (6.2 g, 71.4% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 8.39 (s, 1H), 3.49 (s, 3H), 3.30 (s, 3H).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][N:53]=2)=[CH:48][CH:47]=1>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.O1CCCC1>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([CH3:42])([CH3:44])[CH3:43])=[CH:39][CH:40]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][C:55]([C:58]6[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=6)=[CH:54][N:53]=5)=[CH:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:26][CH:27]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: Brc1ccc(-c2ccc(-c3ccccc3)cn2)cc1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccc(-c6ccccc6)cn5)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Under a stream of argon, 0.35 ml of a hexane solution containing 0.55 mmol of butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C. in which 0.25 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained by Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.15 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 5 ml portion of tetrahydrofuran prepared by dissolving 0.19 g of 2-(4-bromophenyl)-5-phenylpyridine and 0.03 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:chloroform=1:1 to 4:5) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4′-(5-phenylpyridin-2-yl)biphenyl-4-yl]-1,3,5-triazin (0.14 g, yield 43%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: O=[C:2]1O[C:6]2[C:8]3[C:13]([CH2:14][C:5]=2[C:4]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]1[C:20]#[N:21])=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+]>C1COCC1>[N:15]1([C:4]2[C:3]([C:20]#[N:21])=[C:2]3[C:5]([CH2:6][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=43)=[C:6]3[C:8]4[C:13]([CH2:14][C:5]=23)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCCC2)c2c(oc1=O)-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c2c(c3c(c1N1CCCC1)Cc1ccccc1-3)Cc1ccccc1-2

Procedure:
A mixture of 2-oxo-4-(pyrrolidin-1-yl)-2,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (278 mg), indanone-1 (132 mg) and NaH (46 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 158-160° C.; 1H NMR (300 MHz, CDC3) δ 2.01-2.10 (m, 2H, CH2), 3.75-3.85 (m, 4H, 2CH2), 4.12-4.15 (m, 4H, 2CH2), 7.38-7.50 (m, 4H, ArH), 7.58-7.67 (m, 2H, ArH), 7.95 (d, J=7.3 Hz, 1H, ArH), 8.62 (d, J=7.5 Hz, 1H, ArH); IR (KBr) 2199 cm−1 (CN); MS (ESI) 349 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([CH2:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([CH2:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:8][CH2:9][CH2:10][C:6]#[N:7])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)c(CC)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(OCCCC#N)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 182.3 %

Procedure:
Add dropwise, 4-cyano-5-ethyl-3-(4-hydroxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-81) (300 mg, 1.0 mmol) in DMF (10 mL) to a stirring solution of 60% sodium hydride (60 mg, 1.5 Eq.) in DMF (30 mL) at room temperature under a nitrogen atmosphere. After 30 minutes, add dropwise, 4-bromobutryonitrile (179 mg, 1.2Eq.) in DMF (10 mL) to the reaction mixture while continuing to stir at room temperature. After 2 hours, pour mixture into water and extract the desired ether into ethyl acetate. Wash the organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 500 mg as an oil. Purify the material by silica gel chromatography (Chromatotron™) eluting with methylene chloride to provide 333 mg of the title compound as an oil. Mass spectrum (m/e): 366.2 (M*+1): (Bruker 300) 1H NMR δ (CDCl3) 7.27-7.32 (2H, d), 6.87-6.94 (2H , d) 4.03-4.16 (3H, m), 3.85-3.95 (3H, s), 2.78-2.88 (2H, dd), 2.54-2.64 (2H, t), 2.10-2.20 (2H, dd), 1.22-1.33 (4H, m), 1.00-1.10 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[N:34]1([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([C:48]([O:50][CH3:51])=[O:49])[CH2:44][CH2:43]2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:31])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:37]3[CH2:38][CH2:39][N:34]([CH2:40][CH2:41][N:42]4[CH2:43][CH2:44][CH:45]([C:48]([O:50][CH3:51])=[O:49])[CH2:46][CH2:47]4)[CH2:35][CH2:36]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: COC(=O)C1CCN(CCN2CCNCC2)CC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(CCN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added methyl 1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride (190 mg, 0.65 mmol), DIEA (126 mg, 0.97 mmol), HATU (148 mg, 0.39 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 4% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (22.0% up to 31.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 22.0% in 2 min); Detector, UV 254/220 nm. This resulted in 96.5 mg (40%) of the formic acid salt of methyl 1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate as a light yellow solid. LCMS (Method 24) [M+H]+=700.2, RT=2.21 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.59 (s, 3H), 3.49-3.46 (m, 4H), 2.84-2.81 (m, 2H), 2.54-2.52 (m, 6H), 2.50-2.40 (m, 2H), 2.33-2.27 (m, 1H), 2.04-1.99 (m, 2H), 1.88-1.70 (m, 2H), 1.55-1.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].P([O-])([O-])(O)=O.[NH4+].[NH4+]>[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Agent: [Zn]
Product: Clc1cc(Cl)c(Cl)nc1Cl
Yield: 94.1 %

Procedure:
On reaction of 12.76 g (0.05 mol) of pentachloropyridine with 4.1 g (0.063 gram atom) of zinc dust and 10.6 g (0.08 mol) of diammonium hydrogen phosphate using the method described in Example 1, there is obtained 10.2 g (93% of theory) of crude 2,3,5,6-tetrachloropyridine, which contains, according to gas-chromatographical analysis, 95.1% of 2,3,5,6-tetrachloropyridine, 0.8% of 2,3,5-trichloropyridine, 0.5% of 2,3,6-trichloropyridine and 3.6% of pentachloropyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[O:10][C:9]2=[O:24])=[CH:4][CH:3]=1.NC1C=CC(N2[CH2:36][CH:35](COC3C=CC(C(OC)=O)=CC=3)[O:34]C2=O)=CC=1>>[C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[O:10][C:9]2=[O:24])=[CH:4][CH:3]=1)(=[O:34])[CH3:36]
Reactant: Nc1ccc(N2CC(COc3ccc(C(=O)O)cc3)OC2=O)cc1
Reactant: COC(=O)c1ccc(OCC2CN(c3ccc(N)cc3)C(=O)O2)cc1
Product: CC(=O)Nc1ccc(N2CC(COc3ccc(C(=O)O)cc3)OC2=O)cc1
Yield: 88 %

Procedure:
The same procedure of Example 10 was repeated except that 4-[3-(4-aminophenyl)-2-oxooxazolidin-5-yl]methoxy benzoic acid (compound 114) obtained Example 11 was used in lieu of methyl 4-[3-(4-aminophenyl)-2-oxooxazolidin-5-yl]methoxybenzoate to give the title compound (compound 115) in a yield of 88%.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)CO
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C(O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCCCCCN
Solvent: O
Solvent: CCO
Product: CCCCCCNc1cc(Cl)nc(N)n1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
50 g of 2-amino-4,6-dichloropyrimidine were suspended in 350 ml of absolute ethanol in a reactor. 181.5 ml of hexylamine (reagent A) were added in a single portion and the mixture was refluxed for 3 h. The medium was evaporated under vacuum. The oil obtained was taken up in 600 ml of water with stirring for 1 h, 30 min. The precipitate was filtered off, washed and dried in a heated desiccator. 43.5 g of the expected compound were thus obtained, for a yield of 62%.