Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:12][NH2:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:14]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[C:15]=[S:16]>CCO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:12][NH:13][C:15](=[S:16])[NH:14][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1ccc(CN=C=S)cc1
Reactant: NNC(=O)c1ccc2[nH]ccc2c1
Solvent: CCO
Product: COc1ccc(CNC(=S)NNC(=O)c2ccc3[nH]ccc3c2)cc1
Yield: 50.3 %

Procedure:
A solution of 1H-indole-5-carbohydrazide (0.7 g, 3.98 mmol) and 1-isothiocyanatomethyl-4-methoxy-benzene (1.0 g, 5.56 mmol) in EtOH (10 mL) was heated to reflux for 2 h. The solvent was then removed in vacuo and the residue was triturated with EtOH (5 mL) to give 2-(1H-indole-5-carbonyl)-N-(4-methoxybenzyl)-hydrazinecarbothioamide (0.7 g, 2.0 mmol, 51%) as a white solid. MS (ESI, pos. ion) m/z: 355 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC[C@H](O)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@H]1CCN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-((S)-3-hydroxypyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (390 mg, 1.61 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a white solid (244 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 4.40-4.33 (m, 1H); 3.70-3.60 (m, 4H); 3.44-3.34 (m, 1H); 2.88-2.77 (m, 1H); 2.73-2.52 (m, 3H); 2.47 (dd, J=10.1, 5.2 Hz, 1H); 2.30-2.12 (m, 2H); 1.84-1.69 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2([CH2:32][C:33]([NH2:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2([CH2:32][C:33]([NH2:35])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(NC3(CC(N)=O)CCCCC3)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and 2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide in an analogous manner to Example 61e. Product isolated as a pale yellow foam (0.064 g, 24%). MP: 84-96° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.93 (s, 1H), 7.89 (s, 1H), 7.18 (s, 1H), 6.66 (s, 1H), 5.44 (br s, 1H), 5.26 (s, 1H), 5.11 (br s, 1H), 3.86 (s, 3H), 3.66-3.61 (m, 2H), 2.93 (m, 6H), 2.73-2.64 (m, 6H), 2.37-2.29 (m, 2H), 1.72-1.29 (m, 9H). MS: 503.17 (MH)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:16](=[O:27])[NH:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[C:23]([C:21]1[O:20][N:19]=[C:18]([NH:17][C:16]([C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:9]2)=[O:27])[CH:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC[C@H]1C(=O)Nc1cc(C(C)(C)C)on1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
HCl in dioxane (10.0 mL) is added slowly at 0° C. to a solution of (S)-2-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-perhydro-azepine-1-carboxylic acid tert-butyl ester (0.70 g, 1.90 mmol) in DCM (15.0 mL). After stirring the reaction mixture at 0° C. for 3 hours, the solvent is removed under reduced pressure to afford the title product that is used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][CH2:16][CH:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][CH:17]2[CH2:16][OH:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Cc2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cc3ccccc3)cn2)C(CO)C1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A solution of 5-benzyl-2-chloropyrimidine (944 mg, 4.626 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.0 g, 6.939 mmol) and diisopropylethylamine (1.8 g, 13.878 mmol) in dioxane (100 mL) was stirred at 110° C. for two days. The reaction mixture was cooled to room temperature, concentrated and directly purified by silica gel chromatography eluting with petroleum ether:ethyl acetate=1:1, to afford tert-butyl 4-(5-benzylpyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (400 mg, 15%) as a white solid. MS (ES+) C21H28N4O3 requires: 384, found: 385 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[NH:9][C:8](=[O:19])[NH:7][C:6]=1[CH2:20][O:21][CH3:22])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:34]([O:36][C:37]2[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=2)=[O:35])[C:8](=[O:19])[NH:7][C:6]=1[CH2:20][O:21][CH3:22])=[O:4]
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(=O)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reaction time: 0.17 h

Procedure:
To a solution of (+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorophenyl)-pyrimidine (1.98 g, 6.34 mmol) in anhydrous THF (20 mL) at −78° C. under argon atmosphere, a solution of lithium hexamethyldisilazide in THF (1M, 18 mL, 18 mmol) was added over 2-3 min. and the mixture was stirred for 10 min. This solution was added over 6 min. via a cannula to a stirred solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in THF (20 mL) at −78° C. The stirring was continued for 10 min and the mixture was poured onto ice (50 g) and extracted with chloroform (2×50 mL). The combined extracts were dried (sodium sulfate) and the solvent evaporated. The residue was purified by flash column chromatography using hexanes/ethyl acetate (4:1 to 3.5:1) as eluent. The product was obtained as a yellow syrup which on trituration with hexane became white powder (2.4 g, 79%). 1H NMR (CDC13) δ 3.522 (s, 3H), 3.744 (s, 3H), 4.65-4.80 (q, J=16.5 Hz, 2H), 6.323 (s, 1H), 7.10-7.30 (m, 4H), 7.358 (d, J=9 Hz, 2H), 8.273 (d, J=9 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(CN3CCOCC3)cc2)nc1N
Temperature: 70 °C
Yield: 83.5 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.40 g, 2.8 mmol) and 4-morpholin-4-ylmethyl-phenylamine (0.60 g, 3.1 mmol) in acetic acid (15 mL) was heated at 70° C. for 17 h. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH ˜10. The resulting aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a brown syrup (0.70 g, 83%). It was used in the next step without purification. MS (ES+): m/z 300 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[CH:20][C:15]=3[CH:14]=[CH:13]2)[CH2:11][CH2:10]1.[I:21]N1C(=O)CCC1=O>CN(C=O)C>[I:21][C:14]1[C:15]2[CH:20]=[N:19][CH:18]=[N:17][C:16]=2[N:12]([C:9]2([CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:11][CH2:10]2)[CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ncc2ccn(C3(COC4CCCCO4)CC3)c2n1
Solvent: CN(C)C=O
Product: Ic1cn(C2(COC3CCCCO3)CC2)c2ncncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a stirred solution of 7-[1-(Tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine (Preparation 248, 390 mg, 1.43 mmol) in DMF (8 mL) was added N-iodosuccinimide (481.5 mg, 2.14 mmol) and stirred at room temperature for 4 hours. The reaction mixture was quenched with water (8 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water (5×15 mL), brine (10 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 99:1) to afford the title compound as a solid in 79% yield, 450 mg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[CH2:35][CH2:34]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3.76 ml (35.082 mmol) of 4-fluoronitrobenzene are dissolved in 40 mL DMA and combined with 9.25 mL (52.62 mmol) of N-ethyldiisopropylamine and 7.6 ml (38.59 mmol) of 1-(benzyloxycarbonyl)-piperazine. The reaction mixture is stirred for 18 h at 80° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is silica gel and the eluant used is a mixture consisting of cyclohexane:ethyl acetate (50:50).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[Si:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Hydroxybenzaldehyde (70 g, 0.57 mol), tert-butyldimethylsilyl chloride (92 g, 0.61 mol), and imidazole (92 g, 1.35 mol) were combined in dimethylformamide (250 mL). The mixture was stirred at room temperature, under nitrogen, for 1 hour. The solution was poured into water (1.5 L) and extracted with 2×500 mL petroleum ether (35°-60° C. boiling range). The organic solution was washed with saturated sodium chloride solution (100 mL), dried over magnesium sulfate, treated with silica gel (20 g), filtered, and concentrated in vacuo. The residue was dried further under high vacuum to yield (126.6 g (94%) of the air and light-sensitive 3-((tert-butyldimethylsilyl)oxy)benzaldehyde as an amber oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[N:23]1[CH:22]=[C:21]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[CH:20]=[CH:19]3)[CH:26]=[N:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc2cc(-c3cncnc3)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc2cc(-c3cncnc3)ccc2c1
Yield: 83 %

Procedure:
A solution of the product from Example 26C (56 mg, 0.154 mmol) and TBAF.H2O (48 mg, 0.184 mmol, 1.2 equiv.) in THF (3 mL) was stirred at room temperature under a dry nitrogen atmosphere for 30 min. The mixture was then partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was washed with brine then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (32 mg, 83% yield) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:20](I)=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:22])[CH:3]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:20]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:22])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(F)cc1Oc1cc(I)c(N)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(F)cc1Oc1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 242B (3.0 g), bis(triphenylphosphine)palladium(II) dichloride (242 mg), CuI (66 mg) in triethylamine (30 mL) was added trimethylsilylacetylene (2.2 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous NH4Cl, water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the pure product.
Reaction SMILES: C(N[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)C.[CH2:30]([O:32]C1N=C(C(O)=O)C=C(C)N=1)[CH3:31]>>[CH2:30]([O:32][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:31]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Reactant: CCOc1nc(C)cc(C(=O)O)n1
Product: CCOc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{4-[5-(2-Ethoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-ethoxy-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.81 min*; [M+H]+=401.07.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]2[N:20]([C:23](=[O:39])[CH:24]([NH:28]C(OCC3C=CC=CC=3)=O)[CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:22][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]2[N:20]([C:23](=[O:39])[CH:24]([NH2:28])[CH:25]([CH3:26])[CH3:27])[CH2:21][CH2:22][CH:9]12)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)C(N)C(=O)N1CCC2C1C(Oc1ccccc1)CN2C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A 500 mL Parr bottle was charged with crude 14 (410 mg, 0.76 mmol) and 10% Pd-on-carbon (50 mg) in reagent grade MeOH (10 mL). The mixture was pressurized to 50 PSI H2 then shaken for 2 h. The catalyst was removed by filtration through Celite® and the solids were washed with MeOH and EtOAc. The filtrate was concentrated in vacuo to afford 307 mg (quant.) of 15 which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:18])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Br)c(C)cn1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c[n+]([O-])c(C)cc1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
4-Bromo-2,5-dimethylpyridine (500 mg, 2.69 mmol) was added dropwise to a solution of m-chloroperbenzoic acid (816 mg, 3.55 mmol) in dichloromethane (10 mL) at ambient temperature. The mixture was stirred at room temperature for 17 hours, poured into saturated aqueous sodium bicarbonate and sodium sulfite (2 mL, 1.0M), and extracted twice into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow crystralline solid (413 mg) which was used without further purification. LCMS: M+H+=202 & 204.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>>[C:20]([C:23]1[NH:24][N:25]=[C:26]([C:28]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:29])[CH:27]=1)(=[O:22])[CH3:21]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)n[nH]1
Yield: 73.4 %

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (0.50 g, 1.94 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.30 g, 1.94 mmol), HOBt (0.31 g, 2.33 mmol), DIPEA (0.41 ml, 2.33 mmol) and EDCI (0.44 g, 2.33 mmol) using the method of Example 34(d) producing 0.56 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.48 (s, 3H), 3.69-3.73 (m, 2H), 4.39 (t, 2H), 7.05 (d, 1H), 7.30 (s, 1H), 7.88 (d, 1H), 8.18 (d, 1H), 8.32 (d, 1H), 8.66 (d, 1H), 14.16 (s, 1H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:19]([OH:21])=[O:20].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:20][C:19]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]=1[O:7][CH2:19][C:9]1[CH:10]=[CH:11][CH:12]=[CH:17][CH:8]=1)=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc2c(O)cccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2c(OCc3ccccc3)cccc2c1OCc1ccccc1

Procedure:
K2CO3 (2.45 g, 17.7 mmol), Dry DMF (5.4 mL), 1,5-Dihydroxy-naphthalene-2-carboxylic acid (0.539 g, 2.64 mmol), benzyl chloride (1.5 mL) Yield: 0.68 g of product (54%, 2 steps) Rf=0.38 (SiO2, 15% Hexanes/CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 5.12 (s, 2H), δ 5.25 (s, 2H), δ 5.40 (s, 2H), δ 6.98 (d, J=7.3 Hz, 1H), δ 7.30-7.53 (m, 16H), δ 7.83 (d, J=8.7 Hz, 1H), δ 7.89 (d, J=8.7 Hz, 1H), δ 8.14 (d, J=8.7 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1)([O-:3])=[O:2].[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])ccn1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
4-nitropyridin-2-amine (Int-22, 32.4 g, 0.2096 mol) was dissolved in pyridine (200 mL). The reaction was cooled in an ice-water bath and cyclopropanecarbonyl chloride (28.5 mL, 0.314 mol) was added dropwise. Upon completing addition of the acid chloride, the reaction was stirred for 1 hr at 0° C. then warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and then diluted with water. Solids were collected by suction filtration. The filter cake was washed with water and hexanes. The isolated solids were then dried under vacuum to afford N-(4-nitropyridin-2-yl)cyclopropanecarboxamide (43.5 g, 100%). LCMS: (FA) ES+ 208; 1H NMR (300 MHz, CDCl3) δ ppm 8.90 (s, 1H), 8.50 (s, 1H), 8.50 (br s, 1H), 7.7 (dd, 1H), 1.6 (m, 1H), 1.2 (m, 2H), and 1.0 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH:30][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[CH:20][CH:19]=3)=[C:7]3[N:8]=[C:9]([C:13]([OH:15])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.N1C=CC=C[CH:39]=1>CO>[CH:1]1([C:4]2[C:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH:30][S:31]([C:34]([F:36])([F:35])[F:37])(=[O:33])=[O:32])=[CH:22][CH:23]=3)=[C:7]3[N:8]=[C:9]([C:13]([O:15][CH3:39])=[O:14])[CH:10]=[C:11]([CH3:12])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: c1ccncc1
Reactant: Cc1cc(C(=O)O)nc2c(Cc3ccc(-c4ccccc4NS(=O)(=O)C(F)(F)F)cc3)c(C3CC3)nn12
Solvent: CO
Product: COC(=O)c1cc(C)n2nc(C3CC3)c(Cc3ccc(-c4ccccc4NS(=O)(=O)C(F)(F)F)cc3)c2n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 273 mg 2-cyclopropyl-7-methyl-3-[(-2'-(((trifluoromethyl)sulfonyl)amino)biphen-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxylic acid in 150 mL methanol was added 5 g Amberlyst-15. The mixture was heated to 60° C. for 9 hours (overnight generally preferred). After cooling to room temperature, 5 mL pyridine was added and the mixture was stirred for 30 minutes. The mixture was filtered, was stripped of solvent in vacuo, was stripped from toluene, then was chromatographed on silica gel under medium pressure using 1/1/98 HOAc/MeOH/CH2Cl2 to give 91 mg of the title compound (32% yield) as a yellow solid. Rf 0.58 in 1/3/96 HOAc/MeOH/CH2Cl2, visualized by white light, UV, iodine, and ammonium molybdate/ceric sulfate stain.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1CN1CCC(CC(=O)c2ccccc2N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncccc1CN1CCC(CC(=O)c2ccccc2NS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
120 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-aminophenyl)-2-oxoethyl]piperidine obtained in Example 64, 0.1 ml of triethylamine and 0.041 ml of methanesulfonyl chloride were dissolved in 2 ml of dichloromethane, and the mixture was stirred for 2 hours under ice-cooling. An aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 90 mg of the title compound as a yellow oil.