Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([OH:32])[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:47]([Si:51](Cl)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([CH3:50])([CH3:49])[CH3:48].O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O)CC3)n2n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)n2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (800 mg, 1.387 mmol) in DMF (10 mL) at 0° C. was added imidazole (142 mg, 2.081 mmol) followed by tert-butylchlorodiphenylsilane (0.533 mL, 2.081 mmol) and the resulting mixture was stirred at room temp for 16 h. Water (20 mL) was then added and the mixture was extracted with ether (2×25 mL). Ether layer was then washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified via Biotage (0-10% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1 g, 1.227 mmol, 88% yield) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J=8.0, 1.5 Hz, 4H), 7.47-7.28 (m, 6H), 7.01 (s, 1H), 5.82 (br. s., 1H), 4.50-4.38 (m, 2H), 4.31-4.07 (m, 2H), 3.94-3.77 (m, 1H), 3.41-3.24 (m, 3H), 2.61 (s, 3H), 1.88 (br. s., 2H), 1.67 (br. s., 1H), 1.54 (br. s., 1H), 1.51-1.39 (m, 5H), 1.30 (s, 3H), 1.26-1.23 (m, 6H), 1.22 (s, 9H), 1.08 (s, 3H), 1.06 (s, 9H). 4 missing piperidine hydrogens. LCMS (M+H)=816.4.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1C=C[C:11](Cl)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].ClCC(=O)CC1[S:22]C=CC=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[S:22][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(CCl)Cc1cccs1
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1cccs1
Yield: 13 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(thiophen-2-yl)propan-2-one (1.00 g, 5.73 mmol) with acetic acid (0.66 mL, 0.69 g, 12 mmol) and triethylamine (1.60 mL, 1.16 g, 11.5 mmol). Purification by flash chromatography over silica gel (1040% ethyl acetate in hexanes) gave an orange oil (0.144 g, 13% yield): 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H) 3.95 (s, 2H) 4.74 (s, 2H) 6.92-6.94 (m, 1H) 6.99 (dd, J=5.2, 3.4 Hz, 1H) 7.25 (dd, J=5.1, 1.3 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2[N:16]([N:24]=[C:25]([C:27]([OH:29])=O)[CH:26]=2)[C:17]=1/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][C:33]=1[CH3:40].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.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.CO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2[N:16]([N:24]=[C:25]([C:27](=[O:29])[NH:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:40])[CH:34]=3)[CH:26]=2)[C:17]=1/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH3:22])[CH3:23])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1/C=C/CC(C)C
Reactant: Cc1cc(CN)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CNC(=O)c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(/C=C/CC(C)C)n3n2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a mixture of (S,E)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (30 mg, 0.072 mmol) and (4-fluoro-3-methylphenyl)methanamine (20.00 mg, 0.144 mmol) in DMF (1.5 mL) was added DIEA (0.063 mL, 0.359 mmol), HATU (54.6 mg, 0.144 mmol) and DMAP (1.756 mg, 0.014 mmol) and the resulting mixture was stirred at room temp for 16 h. At this point LCMS indicated completion of reaction. Water was then added and the mixture was extracted with ether (25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then treated with 1N NaOH (0.216 mL, 0.216 mmol) in MeOH (1.500 mL) at 60° C. for 5 h. Mixture was then cooled and purified by prep-HPLC to afford (S,E)-2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (12.2 mg, 0.023 mmol, 31.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.91 (t, J=6.4 Hz, 1H), 7.25 (d, J=7.3 Hz, 1.5H), 7.22-7.17 (m, 1.5H), 7.12-7.00 (m, 2H), 6.93 (s, 1H), 5.34 (br. s., 1H), 4.46 (t, J=5.6 Hz, 2H), 2.63 (s, 3H), 2.34 (t, J=6.3 Hz, 2H), 2.22 (s, 3H), 1.88-1.77 (m, 1H), 1.08 (s, 9H), 1.00 (dd, J=6.7, 2.4 Hz, 6H). LCMS (M+H)=511.33.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[OH:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+]>CC#N>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[OH:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1
Yield: 106.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.3 g, 19.5 mmol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (4.5 g, 19.5 mmol), KI (200 mg), NaHCO3 (1.8 g, 21.5 mmol) and CH3CN (125 ml) was stirred at reflux under nitrogen for 24 hours. The cooled reaction was filtered and the filter cake was washed with CH3CN. The filtrate was concentrated to afford an oily residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 8.6 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates prep LC/system 500) to yield 5.0 g. The compound was recrystallized twice from ethanol to provide 3.9 g (49%) of 4-[3-4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-hydroxy-α-methyl-benzene methanol as a light beige solid, m.p.=142°-144° C.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(N(CC)CC)C.Cl>ClCCl.C(O)(C)C.O>[Cl:21][CH2:20][CH2:19][CH2:18][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:6][CH:7]=2)[CH2:12]1
Reactant: ClCCCBr
Reactant: CCC(=O)c1ccc2c(c1)CNCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)c1ccc2c(c1)CN(CCCCl)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The isomer mixture from step 1.3 (0.27 mol, 63.4 g) was suspended in 634 ml of dichloromethane. The base was liberated from the hydrochloride by adding 1.05 eq of sodium hydroxide solution and 317 ml of water and separating the phases. After phase separation and extraction of the aqueous phase with a little dichloromethane, the combined organic phases were washed once with 50 ml of water, filtered and concentrated several times in a rotary evaporator. The residue was dissolved in dimethylformamide, and 1-bromo-3-chlorpropane (0.68 mol, 107.4 g) and triethylamine (0.55 mol, 55.3 g) were added successively to the solution. It was then stirred at room temperature for 16 h, 760 ml of water were added to the resulting suspension, and it was extracted twice with about 300 ml of dichloromethane. The combined organic phases were washed once with 100 ml of water, filtered and concentrated under reduced pressure. The residue was dissolved in 61 ml of methanol and 410 ml of methyl tert-butyl ether. 1.2 equivalents of hydrogen chloride in isopropanol are added drop-wise thereto. The mixture was briefly boiled and then slowly cooled to room temperature. The precipitate was filtered filtered off sucked air through until it was good. This resulted in 87 g of crude product which was recrystallized twice from methanol. This resulted in 26.7 g of the title compound (7 isomer:6 isomer: 97:3 (via 13C-NMR)).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[N+]=[N-].CP(C)C.O>O1CCCC1>[C:13]1([C:12]#[C:11][C:9]2[CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7][CH:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1cncc(C#Cc2ccccc2)c1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: NCc1cncc(C#Cc2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of 3-(azidomethyl)-5-(phenylethynyl)pyridine (7.8 g, 33.3 mmol) in tetrahydrofuran (101 mL) at 0° C. was added trimethylphosphine (1M in tetrahydrofuran, 49.9 mL, 49.9 mmol). After evolution of nitrogen had slowed, the ice bath was removed and stirring continued for 1 h. To this was added water (6.0 mL, 333 mmol) and the mixture stirred at room temperature for 2 h. The reaction was concentrated, dissolved in ether, washed with water (5×), then brine, dried over potassium carbonate, filtered, and concentrated to give 5.96 g (77%) as a faint yellow solid which was used without purification. 1H NMR (CDCl3) δ: 8.67 (d, J=1.8 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 7.53-7.61 (m, 2H), 7.35-7.44 (m, 3H), 3.95 (s, 2H), 1.45 (d, J=5.2 Hz, 2H)1H NMR (CDCl3) δ: 8.67 (d, J=1.8 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 7.53-7.61 (m, 2H), 7.35-7.44 (m, 3H), 3.95 (s, 2H), 1.45 (d, J=5.2 Hz, 2H). 13C NMR (CDCl3) δ: 150.8, 147.9, 137.8, 137.4, 131.8, 128.9, 128.6, 122.7, 120.3, 92.7, 86.1, 43.7. Mass spec.: 209.1 (MH)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].N([O-])=O.[Na+].CCOC(C)=O.[ClH:23]>O.[Cu](Cl)Cl.[Cu]Cl>[Cl:23][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6]
Reactant: Cl
Reactant: Nc1cc(CO)cc([N+](=O)[O-])c1
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(CO)c1
Temperature: -5 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a suspension of 3-amino-5-nitrobenzyl alcohol (103.8 g, 0.62 mol; from step (ii) above) in 1.0 L of 6N HCl at −5° C. was added sodium nitrite (47.1 g, 0.68 mol) in H2O (400 mL) over 45 min. The resulting solution was stirred at −5° C. for 1 h prior to the addition of a mixture of copper(II)chloride (125.0 g, 0.93 mol) and copper(I)chloride (0.74 g, 0.007 mol) in 6N HCl (1.0 L) over 1 h while maintaining the temperature at less than 0° C. The resulting solution was warmed to 60-70° C. for 2.5 h then cooled to room temperature and extracted with Et2O (6×). The organics were washed with brine (2×), dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. Flash chromatography on silica gel eluting with Hex:EtOAc (4:1) gave 81.7 g (70%) of the sub-title compound as an off white solid. The sub-title compound could be further purified by crystallization from CH2Cl2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([CH2:13][C:14]2[C:15]([NH2:21])=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2COCC[Si](C)(C)C)[CH3:2].CC([O-])(C)C.[K+].C(OC1C=C(C=O)C=C2C=1C=CN2COCC[Si](C)(C)C)C.N(CCC#N)C1C=CC=CC=1.Cl.NC(N)=N>C(O)(C)(C)C.CS(C)=O.C(O)C.O>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([CH2:13][C:14]2[C:15]([NH2:21])=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH3:2]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc2c1ccn2COCC[Si](C)(C)C
Agent: CC(C)(C)[O-]
Agent: CCOc1cc(C=O)cc2c1ccn2COCC[Si](C)(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc2[nH]ccc12
Reaction time: 2 h
Yield: 62 %

Procedure:
5-[4-Ethoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-6-ylmethyl]-pyrimidine-2,4-diamine. A warm solution of potassium tert-butylate (900 mg, 8.02 mmol) in tert-butanol (7.5 mL) was added at room temperature to a solution of 4-ethoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-6-carbaldehyde (2.14 g, 6.69 mmol) and 3-anilinopropionitrile (1.08 g, 7.36 mmol) in methyl sulfoxide (25 mL). After 90 min the solution was treated with water and the suspension formed was stirred for 2 h. The precipitate was collected by filtration and dried. This material was added to a suspension of guanidine hydrochloride (1.90 g, 19.9 mmol) and potassium tert-butylate (2.23 g, 19.9 mmol) in ethanol (100 mL), and the reaction mixture was refluxed for 16 h, then most of the solvent was distilled off, and ether (50 mL) was added. Insoluble material was removed by filtration, the filtrate was washed with water, dried (MgSO4), and evaporated. The residue was washed with diethyl ether/n-hexane 4:3 (70 mL) to afford the title compound (1.71 g, 62%). Light brown solid.
Reaction SMILES: CC1C=CC(S(NN)(=O)=O)=CC=1.[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:21]1[S:22][C:23]2[C:28]([N:29]=1)=[CH:27][CH:26]=[C:25]([C:30]1([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:33][C:32](=O)[CH2:31]1)[N:24]=2.C([BH3-])#N.[Na+].C1COCC1>CO.[Cl-].[Zn+2].[Cl-]>[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:21]1[S:22][C:23]2[C:28]([N:29]=1)=[CH:27][CH:26]=[C:25]([C:30]1([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:31][CH2:32][CH2:33]1)[N:24]=2
Reactant: Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC(=O)C4)nc3s2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CCC4)nc3s2)c(F)c1
Temperature: 70 °C

Procedure:
To a thick slurry of p-methylbenzenesulfonylhydrazine (0.036 g, 0.19 mmol) and 3-(2-(2-fluoro-4-methylphenyl)thiazolo[5,4-b]pyridine-5-yl)-3-phenylcyclobutanone (0.050 g, 0.13 mmol) in 0.3 mL MeOH under nitrogen was added a pre-mixed suspension of sodium cyanoborohydride (0.016 g, 0.26 mmol) and zinc chloride, 0.5 M solution in THF (0.26 mL, 0.13 mmol) in 0.26 mL MeOH, via pipette. The reaction mixture was sealed and heated to 70° C. for 3 h. The reaction mixture was adsorbed onto 600 mg silica gel and dried. Purification by silica gel chromatography, 12 g, 0-50% EA/hexanes provided 2-(2-fluoro-4-methylphenyl)-5-(1-phenylcyclobutyl)-thiazolo[5,4-b]pyridine as a light yellow oil that slowly solidified. MS (ESI) m/z: calculated: 374.1; Observed: 375.1 (M++1).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][CH2:11][C:12](O)=[O:13])[CH2:5][CH2:4]1.[CH3:28][NH:29][CH3:30].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C1COCC1>[CH3:28][N:29]([CH3:30])[C:12](=[O:13])[CH2:11][CH2:10][O:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:5]1
Reactant: CN([C@H]1CC[C@H](OCCC(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C

Procedure:
g (2.7 mmol) trans-3-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid in 30 ml CH2Cl2 were treated with 2 ml (4.0 mmol, 1.5 eq) 2M dimethylamine in THF and 0.44 ml (4.03 mmol, 1.5 eq) NMM. The solution was cooled to 0° C. and 670 mg (3.5 mmol, 1.3 eq) EDCI and 82 mg (5.4 mmol, 0.2 eq) HOBT were added. The mixture was stirred at RT over night, partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc gave 1.06 g (90%) trans-N,N-Dimethyl-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionamide as white solid, mp 88° C., MS: 437 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:45])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[B-](F)(F)(F)F.CCO[C:54]([C:56]([C:66]#N)=[N:57]OC(N(C)C)=[N+](C)C)=O.C(N)(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C.O.C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:45])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:32]3([C:36](=[O:37])[NH:57][CH:56]([CH3:66])[CH3:54])[CH2:35][CH2:34][CH2:33]3)[N:28]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)O)CCC3)n(-c3ccccc3)n2)CC1
Agent: F[B-](F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)NC(C)C)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-(1-carboxy-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 0.3 ml of DMF, 28 mg of TOTU, 36 mg of NEM and 10 mg of isopropylamine was added. The reaction mixture was allowed to stir at RT for 16 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. This residue was dissolved in 1 ml of DCM, 0.2 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was dissolved in 3 ml of water and lyophilized to yield a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:20](=[O:21])[CH2:19][CH2:18][Cl:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: COc1ccc(NC(=O)CCCl)cc1
Temperature: 10 °C
Yield: 66.1 %

Procedure:
A three-necked flask-was charged with p-Anisidine (50 g), Et3N (40.43 g) and methyl ethyl ketone (100 ml). The resulting slurry was cooled to 10° C. and 3-chloropropionyl chloride (50.74 g) was slowly added. The temperature was allowed to rise to 60° C. during the addition. The mixture was then refluxed for 1 hour and cooled to 50° C. The solids were collected by filtration, washed with water, and dried at 50° C. to constant weight to give N-(4-methoxyphenyl)-3-chloropropionamide (56.42 g, 86.8%).
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)=[CH:10]2)=[N:5]1)([CH3:3])[CH3:2].N[C@H](C(O)=O)CCSC.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CS(O)(=O)=O.O>[CH:1]([N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:13][C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)=[CH:10]2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2ccc3nn(C(C)C)cc3c2)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Solvent: O
Product: CC(C)n1cc2cc(Oc3ccc(O)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
A solution of 2-Isopropyl-5-(4-methoxy-phenoxy)-2H-indazole (0.075 grams, mmol) in 2 mL of methanesulfonic acid was treated with 0.15 grams of methionine. After stirring for 24 hours at room temperature, the mixture was treated with 1.2 grams of sodium hydroxide in 25 mL of water with cooling in an ice bath, neutralized with aqueous sodium bicarbonate, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, affording 0.070 grams of 4-(2-Isopropyl-2H-indazol-5-yloxy)-phenol as a colorless syrup. MS: 269.7 [M+H]+
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[F:39])[C:33](Cl)=[O:34]>>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[F:39])[C:33]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:34]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(F)c(F)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,4-difluorobenzoyl chloride: ESMS m/e: 520.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[N:13]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:12]3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].C[Si]([C:25]#[CH:26])(C)C.[F-].C[N+](C)(C)C.O>C(N(CC)CC)C.O1CCCC1.C(OCC)(=O)C.[Cu]I>[CH2:1]([CH:3]([N:6]1[C:14]2[N:13]3[N:15]=[C:16]([CH3:19])[C:17]([C:25]#[CH:26])=[C:12]3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(I)c(C)nn3c21
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#Cc1c(C)nn2c3c(c(C)nc12)CCN3C(CC)CC
Reaction time: 0.17 h
Yield: 48.7 %

Procedure:
A solution of 8-(1-ethylpropyl)-3-iodo-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (2.0 g, 5.29 mmol), trimethylsilylacetylene (0.8 mL, 5.82 mmol), Cl2Pd(PPh3)2 (0.19 g, 0.26 mmol) and copper (I) iodide (50 mg, 0.26 mmol) in triethylamine (20 mL) was stirred at room temperature for two hours. The solution was filtered through Celite, and the filtrate was evaporated. Tetramethylammonium fluoride (1.0 M tetrahydrofuran solution 6.3 mL, 6.3 mmol) was added to a solution of the residue in tetrahydrofuran (20 mL) at room temperature, followed by stirring for 10 minutes. Water was added thereto, and the mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10-20% ethyl acetate/hexane), to give the title compound (727 mg) as pale brown crystals.