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][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCNC2)CC1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
4-[2-(Piperidin-3-yloxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Preparation 49A, Step 2) (340 mg, 0.94 mmol) was dissolved in CH2Cl2 (15 mL) under nitrogen and cooled to 0° C. Isobutyryl chloride (0.29 mL, 2.82 mmol) was added followed by dropwise addition of triethylamine (0.52 mL, 3.76 mmol). The mixture was warmed to r.t. and stirred for about 16 hours. Methylene chloride (20 mL) was added, and the solution was washed with saturated NaHCO3 (20 mL)and brine (20 mL), and then dried over magnesium sulfate. The solvents were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:1), to afford the final compound as a white solid (322 mg, 80%). TLC (SiO2): Rf=0.42 (1:1 ethyl acetate/hexanes)
Reaction SMILES: [NH2:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>O1CCCC1.O>[CH:36]1([C:39]([NH:1][C:2]2[N:28]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[CH:13][C:14]([CH3:27])=[C:15]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:40])[CH2:38][CH2:37]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2C)n(C)n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)n(C)n1
Yield: 60 %

Procedure:
To a solution of N-{5-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (158 mg, 0.419 mmol) and triethylamine (63.8 μL, 0.461 mmol) in tetrahydrofuran (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (41.9 μL, 0.461 mmol), and the mixture was stirred at room temperature for 1 hr. Cyclopropanecarbonyl chloride (83.8 μL, 0.922 mmol) was further added and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, sodium carbonate (200 mg), methanol (3 mL) and water (100 μL) were added to the residue, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate to give the title compound (112 mg, 60%) as a white solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])OCC[O:13]3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:13])[CH3:17])=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC1(c2ccc(-c3cnco3)cc2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(-c2cnco2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[4-(5-oxazolyl)phenyl]-2-methyl-1,3-dioxolane (711 mg, 3.08 mmol) in acetone (18 ml) and water (2.8 ml) was added pyridinium p-toluenesulfonate (116 mg, 0.46 mmol), and the mixture was heated at reflux temperature for 8 hours. The mixture was cooled down to room temperature, and concentrated in vacuo. The residue was dissolved in diethylether and washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The compound was used for next reaction without purification.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O.[CH:40]([C:43]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([CH3:52])[CH3:51])[C:44]=1[NH2:45])([CH3:42])[CH3:41]>O.CN(C=O)C>[CH:50]([C:46]1[CH:47]=[CH:48][CH:49]=[C:43]([CH:40]([CH3:42])[CH3:41])[C:44]=1[NH:45][C:37](=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][OH:22])([CH3:52])[CH3:51]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.7 %

Procedure:
WSC (4.2 g, 22 mmols) and HOBt (3.0 g, 22 mmols) were added to a DMF (40 ml) solution of the resulting carboxylic acid (5.2 g, 20 mmols) and 2,6-diisopropylaniline (5.3 g, 30 mmols), and stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the precipitate formed was taken out through filtration, and extracted with chloroform. The organic layer was washed with 1 N HCl and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. The residue was extracted with ether and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1) to obtain 1.9 g (yield: 23%) of N-(2,6-diisopropylphenyl)-15-hydroxypentadecanamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>C(#N)C>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:11]2[S:10][CH2:16][C:14](=[O:15])[N:13]=2)=[N:4][CH:5]=1
Reactant: Cc1cnc(CN)cn1
Reactant: O=C1CSC(=S)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CNC2=NC(=O)CS2)cn1
Temperature: 0 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
To a solution of 2-(aminomethyl)-5-methyl-pyrazine (3.69 g, 30 mmol) and Rhodanine (3.59 g, 27 mmol) in acetonitrile (100 mL) was added DIPEA (10.45 mL, 60 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (8.15 g, 30 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in acetonitrile (25 mL) at hot condition. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with acetonitrile. After drying in air, 1.5 g (25% yield) of 2-[(5-methyl-pyrazin-2-ylmethyl)-amino)-thiazol-4-one was isolated as a white solid: HRES(+) m/e calcd for C9H10N4OS (M+H)+ 223.0648. found 223.0648.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5](I)[CH3:6].[C:8]([C:10]1[S:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[F:29])[CH:11]=1)#[CH:9]>CS(C)=O.O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:5]([N:1]1[CH:9]=[C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=3[F:29])[CH:11]=2)[N:3]=[N:2]1)[CH3:6]
Reactant: CCI
Reactant: C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of NaN3 (107.3 mg, 1.65 mmol) in DMSO (5 ml) was added ethyl iodide (257 mg, 1.65 mmol) and the reaction mixture was stirred for 12 hrs at RT. The alkyne 410 (520 mg, 1.65 mmol) and Cu(OAc)2×H2O (66 mg, 0.2 eq, 0.331 mmol) were added and the deep red reaction mixture was allowed to stir at RT overnight. After 72 hrs, an orange precipitate had formed. The mixture was diluted with water and the solid was collected by filtration. The orange solid 413 was used directly in the next step with no additional purification (620 mg, 97% yield). LCMS: 386.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18])[CH:8]=2)[N:3]=1.[Cl:21][C:22]1[CH:41]=[CH:40][CH:39]=[CH:38][C:23]=1[CH2:24][NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([N:25]([CH2:24][C:23]3[CH:38]=[CH:39][CH:40]=[CH:41][C:22]=3[Cl:21])[CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([O:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29]3)(=[O:19])=[O:18])[CH:8]=2)[N:3]=1
Reactant: COCOC1CCN(CCNCc2ccccc2Cl)CC1
Reactant: O=S(=O)(Cl)CCCCOc1ccc2nc(Cl)ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC1CCN(CCN(Cc2ccccc2Cl)S(=O)(=O)CCCCOc2ccc3nc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
1.75 g of 4-(2-chloro-6-quinolyloxy)butylsulfonyl chloride was added, at 0° C., to a solution of 1.6 g of 1-[2-(2-chlorobenzylamino)ethyl]-4-methoxymethoxypiperidine and 1 ml of triethylamine in 25 ml dichloromethane. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/dichloromethane) to obtain 2.63 g of 2-chloro-6-[4-{N-(2-chlorobenzyl)-N-[2-(4-methoxymethoxy-1-piperidinyl)-ethyl]aminosulfonyl}butoxy]quinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].[CH3:25][C:26]1[NH:27][CH:28]=[C:29]([CH:31]=O)[N:30]=1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([NH:1][CH2:31][C:29]3[NH:30][C:26]([CH3:25])=[N:27][CH:28]=3)=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COc1ccccc1CN
Reactant: Cc1nc(C=O)c[nH]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1ccccc1CNc1ccc2c(NCc3cnc(C)[nH]3)cccc2n1

Procedure:
The title compound, MS: m/e=374.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 2-methoxybenzylamine and 2-methyl-1H-imidazole-4-carbaldehyde as described in example 26.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([Cl:21])=[O:20]>C(N(CC)CC)C>[ClH:21].[N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][N:8]2[C:19](=[O:20])[CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCN(CC2CSCCN2)C1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(Cc1cccs1)N1CCSCC1CN1CCCC1
Yield: 19.9 %

Procedure:
The procedure described in Example 17 was repeated, but using 1.0 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, 2.49 ml of triethylamine and 1.03 g of 2-thienylacetyl chloride, to afford 0.37 g of the title compound, melting at 204°-206° C. (dec.).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:24])=O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.Cl.[C:26]1(/[CH:32]=[CH:33]/[C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([N:37]3[CH2:36][CH:35]=[C:34]([CH:33]=[CH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:39][CH2:38]3)=[O:24])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: C1=C(/C=C/c2ccccc2)CCNC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc2[nH]ccc2c1)N1CC=C(C=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.77 g, 4.02 mmol) was added to a mixture of indole-5-carboxylic acid (0.45 g, 2.79 mmol), (E)-4-(2-phenylethenyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.59 g, 2.66 mmol), 1-hydroxybenzotriazole hydrate (0.56 g, 3.3 mmol) and triethylamine (1.1 ml, 7.9 mmol) in dimethylformamide (20 ml). The reaction mixture was stirred at room temperature, under nitrogen, overnight then poured into water (200 ml) and extracted with ethyl acetate (2×100 ml). The extracts were washed with 1M hydrochloric acid (2×100 ml), saturated brine (100 ml), combined and dried (MgSO4). The residue after evaporation of the solvent was purified by flash chromatography, eluting with 2:1, 3:1 then 4:1 ethyl acetate/petrol (60°-80°), to afford the title compound as an off-white solid (0.55 g, 63%); δH (CDCl3) 2.50 (2H, br s, tetrahydropyridinyl CH2), 3.76 (2H, v br s, tetrahydropyridinyl CH2), 4.31 (2H, v br s, tetrahydropyridinyl CH2), 5.84 (1H, v br s, tetrahydropyridinyl CH), 6.51 (1H, d, J 16.2 Hz, CH=CHPh), 6.60 (1H, br s, 3'-H), 6.81 (1H, d, J 16.2 Hz, CH=CHPh), 7.20-7.42 (9H, m, ArH), 7.42 (1H, s, ArH), and 8.46 (1H, br s, NH).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](C1NC=CN=1)([C:21]1[NH:22][CH:23]=[CH:24]N=1)=O.C(NCC)C.O>O1CCCC1>[CH2:21]([N:22]([CH2:23][CH3:24])[C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([NH:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:11]=1)[CH3:19]
Reactant: CC(C)(C)OC(=O)CNc1cccc(C(=O)O)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cccc(NCC(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 3-(N-tert-butoxycarbonylmethylamino)benzoic acid (10.0 g, 39.8 mmol) in 100 mL of tetrahydrofuran was added carbonyl diimidazole (6.78 g, 41.8 mmol) under Argon. After 2 h of stirring, diethylamine (5.82 g, 79.4 mmol) was added, and the reaction mixture was stirred for 18 h and then refluxed 3 h. After cooling, water (50 mL) was added to the reaction flask, and the contents were concentrated on a rotary evaporator. The resulting mixture was extracted three times with dichloromethane (50 mL). These extracts were combined, washed twice with 1 N aqueous hydrochloric acid solution (50 mL) and twice with water (50 mL), dried (Na2SO4), and concentrated to give 11.9 g (98%) of N,N-diethyl 3-(N-tert-butoxycarbonylmethylamino)benzamide as a yellow oil. MS (ES), m/z 307 (MH+). 300 MHz 1H NMR (CDCl3) δ1.03-1.19 (br m, 3H), 1.15-1.30 (br m, 3H), 1.45 (s, 9H), 3.14-3.31 (br m, 2H), 3.45-3.62 (br m, 2H), 4.33 (d, J=5.6 Hz, 1H), 4.95 (br s, 1H), 7.19-7.38 (m, 4H).
Reaction SMILES: C1C2C(OC(=O)[N:16](C)[C@@H:17]([CH2:40][S:41][CH2:42][C@H:43]([NH:58][C:59](=[O:71])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:18](=[O:39])[NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][P:31]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])=[O:32])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1.CN(C=O)C>[NH2:16][C@@H:17]([CH2:40][S:41][CH2:42][C@H:43]([NH:58][C:59](=[O:71])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:18](=[O:39])[NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][P:31](=[O:32])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@@H](C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)N(C)C(=O)OC1c2ccccc2-c2ccccc21)NC(=O)CCCCCCCCCCC
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ((9H-fluoren-9-yl)methyl((14R,18R)-1-(diethoxyphosphoryl)-18-dodecanamido-13-oxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontan-14-yl)carbamate (1 eq) was added 20% piperidine (50 eq) in 4:1 THF/DMF. The resulting solution was stirred for 15 minutes at 25° C. and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[NH3:22]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH2:22])=[O:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClP(Cl)Cl
Product: Cc1ccc(Oc2ccccc2C(N)=O)cc1

Procedure:
2-[4-Methylphenoxy]benzoic acid, prepared as described by D. J. Carini in J. Medicinal Chem., 33, 1330- (1990), is converted to the corresponding acid chloride with phosphorous trichloride in benzene. The acid chloride is reacted with ammonia to give 2-(4-methylphenoxy)-benzenecarboxamide. The carboxamide is then dehydrated by treatment with thionyl chloride to give 2-(4'-methylphenoxy)benzonitrile.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH:27]1[C:35]2[C:30](=[CH:31][C:32](C(O)=O)=[CH:33][CH:34]=2)C=N1.[OH:39][C:40]1[C:48]2N=NN[C:44]=2[CH:43]=CC=1.C(N(CC)CC)C.NC1C=CC(N2CCC(O)CC2)=CC=1.C(Cl)CCl>CN(C=O)C>[CH:48]1([C:40]([NH:27][C:35]2[CH:30]=[CH:31][C:32]([N:22]3[C:23]4[C:19](=[CH:18][C:17]([C:15]([NH:14][C:11]5[CH:10]=[CH:9][C:8]([N:5]6[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]6)=[CH:13][CH:12]=5)=[O:16])=[CH:25][CH:24]=4)[CH:20]=[N:21]3)=[CH:33][CH:34]=2)=[O:39])[CH2:43][CH2:44]1
Reactant: O=C(Nc1ccc(N2CCC(O)CC2)cc1)c1ccc2[nH]ncc2c1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: Oc1cccc2[nH]nnc12
Agent: Cl
Agent: Nc1ccc(N2CCC(O)CC2)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCC(O)CC2)cc1)c1ccc2c(cnn2-c2ccc(NC(=O)C3CC3)cc2)c1

Procedure:
Compound 945 was prepared according to the general procedure described in Scheme IV. Preparation of N-(4-(4-hydroxypiperidin-1-yl)phenyl)-1H-indazole-5-carboxamide: 1H-indazole-5-carboxylic acid hydrochloride (100 mg, 0.50 mmol), hydroxybenzotriazole (7 mg, 0.05 mmol), triethylamine (0.2 mL, 1.3 mmol), and 1-(4-aminophenyl)piperidin-4-ol (193 mg, 1.00 mmol) were taken up in DMF (2.51 mL) and stirred. EDC (106 mg, 0.05 mmol) was added to the solution last. After the addition, the solution was stirred at room temperature for 24 h. The solution was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. Filtration and concentration gave the crude amide. Purification via flash chromatography 0-10% MeOH/CH2Cl2 gave 55 mg (32%) of the product as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O.O>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:7][N:8]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1nn(C(=O)OC(C)(C)C)c2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C(=O)OC(C)(C)C)c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.7 %

Procedure:
The mixture of 1-tert-butyl 3-ethyl 6-bromo-1H-indazole-1,3-dicarboxylate (1.3 g), p-nitrophenyl boronic acid (666 mg), Pd (dppf)Cl2 (92 mg), and potassium carbonate (1 g) in N,N-dimethylformamide/water (4:1, 20 Ml) was stirred at room temperature for 24 h. Ethyl acetate and water were added. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, EA only) to give 1-tert-butyl 3-ethyl 6-(4-nitrophenyl)-1H-indazole-1,3-dicarboxylate (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(=O)(O[CH2:20][CH2:21][SH:22])OCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][SH:22])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)OCCS
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(CC2CCN(CCS)CC2)cc1

Procedure:
A mixture of 4-(4-fluorobenzyl)piperidine (5.9 g, 30.5 mmol) and ethyl 2-mercaptoethyl carbonate (4.8 g, 32 mmol) was heated to reflux in toluene (250 mL) for 18 hr under a nitrogen atmosphere. The toluene was removed in vacuo and the resulting oil was used without purification in the next step.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].S(Cl)(=O)(=O)N.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+].[Cl-]>CN1C(=O)CCC1.C(O)=O>[C:13]1([O:19][S:2](=[O:3])(=[O:4])[NH2:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1
Agent: NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O=CO
Product: NS(=O)(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A three necked round bottom equipped with a reflux condenser was charged with chlorosulfonyl isocyanate (5.25 ml, 0.06 mol) and cooled to 0° C. Formic acid (2.25 mL, 0.06 mol) was added dropwise with rapid stirring with rapid gas evolution observed. Upon complete addition of formic acid, the reaction was let warm to room temperature. After 2 h, the resultant reaction vessel containing the solid sulfamoyl chloride was cooled to 0° C. and phenol (1.88 g, 0.02 mol) dissolved in NMP (25 mL) was added dropwise via an addition funnel. The reaction was let warm to room temperature. After 3 h stirring, the reaction mixture was poured into cold saturated aqueous NaCl (120 mL) and extracted with EtOAc. After removal of the separated organic solvent, the crude product was purified by column chromatography on silica (35% EtOAc/hexane) to provide sulfamic acid phenyl ester (2.8 g, 81%): LCMS found 173.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[N:3]=1.C1COCC1.O.[OH-].[Li+]>CO>[OH:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[N:3]=1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn2ccc(O)nc12
Yield: 68.3 %

Procedure:
To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A; 2.0 g, 9.65 mmol) in a 2:1 mixture of THF:MeOH, (40 mL) was added lithium hydroxide monohydrate (29 mL, 29.0 mmol, 1.0 M in water). The solution was stirred at reflux for 16 hours then cooled and concentrated. The residue was dissolved in water (100 mL) and acidified with 6M HCl. The resulting white precipitate was collected by filtration and washed with water and Et2O, then dried under reduced pressure to afford 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.18 g, 68% yield) as a white solid. 1H NMR (d6-DMSO) δ 8.50 (d, 2H, J=7.7 Hz), 8.02 (s, 2H), 6.07 (d, 2H, J=8.2 Hz)