Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O.C(N(CC)CC)C.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:28])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)[C@@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a 12-L 3-neck flask with a mechanical stirrer, an addition funnel, and a thermometer were added 400 g (3.414 mol) of D-valine (36.0), 3 L of water, 380 mL of THF, and 1190 mL (8.572 mol) of triethylamine (TEA). To this solution was added dropwise at 5°-10° C. a solution of 774 g (3.414 mol) of 2-naphthalenesulfonyi chloride (35.0) in 800 mL THF. The mixture was allowed to warm to room temperature and stirred for 2 hours. Evaporation of THF followed by quenching into 4 L of 3 N HCl precipitated crude product. Crystallization of the crude product from t-butyl methyl ether gave 910 g (87%) of 18.1. M.p: 170°-172° C. (literature gives the m.p. as 170°-172° C.-see Kiyooka, S.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M. J. Org. Chem., 1991, 56, 2276.). The spectrum data are identical to that of the literature.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:15]=[CH:14][C:13]=2[Cl:27])=[CH:8][CH:7]=1)=[O:5])C>C(O)C.[OH-].[Na+]>[CH:21]1([C:19]([NH:18][C:16]2[CH:15]=[CH:14][C:13]([Cl:27])=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=3)[CH:17]=2)=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of 5′-(cyclohexanecarbonyl-amino)-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (200 mg) in ethanol (15 ml) and 1M sodium hydroxide (7.5 ml) was stirred at 20 C for 18 h. The ethanol was then evaporated and the residue acidified. The solid thus formed was collected by filtration and dried (176 mg).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[O:10][C@@H:9]1[CH2:11][OH:12].[N+:13]([C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C1OC1CO>ClCCl>[CH2:8]1[O:10][C@@H:9]1[CH2:11][O:12][S:22]([C:18]1[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=[CH:20][CH:19]=1)(=[O:23])=[O:24]
Reactant: OC[C@@H]1CO1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: OCC1CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 250 ml rounded bottom flask was charged with triethylamine (3.3 g, 4.5 ml, 32 mmol), R-glycidol (2.0 g, 27 mmol)(Arco Company, Newton Square, Pa.) and dichloromethane (50 ml) then cooled to 0° C. A solution of 3-nitrobenzenesulfonyl chloride (6.0 g, 27 mmol) in dichloromethane (40 ml) was added dropwise over a 5-minute period to the glycidol solution and the reaction mixture was stirred at 0° C. under N2 for 3 hrs. The reaction mixture was poured into a separatory funnel and washed successively with 1N aqueous hydrochloric acid (90 ml), 5% aqueous sodium bicarbonate solution (90 ml), and saturated aqueous sodium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo to yield (2S)-(+)-glycidyl-3-nitrobenzenesulfonate as a pale colored solid. Recrystallization from hexanes/EtOAc (1:1, 50 ml) provided 5.89 g (83%) of pure (2S)-(+)-glycidyl- 3-nitrobenzenesulfonate, m.p. 61°-63° C., [α]D +22.3°(c 0.41, chloroform), >95% optical purity.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[Br:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:32](=O)[O:31][CH2:30]2.Cl>C(COC)OC.O.C1COCC1>[Br:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:32](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:31][CH2:30]2
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=C1OCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
To a stirred solution of oxindole (3.13 g, 23.5 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 1.0M LiHMDS/THF solution (49 ml, 49 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-bromophthalide (3.00 g, 14.1 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then poured into a mixture of THF (50 ml) and 2M HCl aqueous solution (50 ml). After heated at reflux for 1 hour and then cooled to room temperature, the resulting mixture was poured into water (100 ml). The resulting solid was filtered, washed with water and dried under vacuum to give 3-(5-bromo-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as a yellow solid (3.57 g, 77%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH:16][C:17](=O)[CH2:18][NH:19][CH2:20][CH2:21][C:22]2[N:23](CCO)[CH2:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(P(CCCC)CCCC)CCC.[CH3:63][C:64]([O:67]C(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH3:1][S:2]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[N:16]2[CH2:17][CH2:18][N:19]([CH2:20][CH2:21][C:22]3[N:23]=[CH:24][N:25]([C:27]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:26]=3)[CH2:63][C:64]2=[O:67])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CNCCC3=CN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CN3CCO)c2c1
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc2cccc(N3CCN(CCc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)CC3=O)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.2 %

Procedure:
To a solution of the product from Step F (60.5 mmol) in 500 mL of tetrahydrofuran was added tributylphosphine (25 mL, 100 mmol). After cooling to 0° C., di-tert-butylazodicarboxylate (23 g, 100 mmol) was added, and the reaction was allowed to come to room temperature for 2 hours. The solution was concentrated in vacuo, partitioned between EtOAc and water, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product (45.0 g). The crude product was purified by silica gel chromatography (5% MeOH/CHCl3) to provide the pure titled product along with impure fractions.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][NH:12][C:4]=2[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.S(C1C=CC(C)=CC=1)(O)(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[C:11]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[NH:12][C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: N#Cc1nc(Cl)cc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nc(Cl)cc2[nH]c(C3CCCCO3)nc12
Temperature: 60 °C

Procedure:
6-Chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1 g) was dissolved in ethyl acetate (20 ml). To above solution was added 3,4-dihydro-2H-pyran (1 ml) and tosylic acid hydrate (50 mg). The mixture was heated at 60° C. for 10 hours, than washed with sodium bicarbonate (5%, 10 mL). The organic layer dried over sodium sulphate, solvent removed to give the title compound. 1H NMR (DMSO) □ 8.92 (s, 1H), 8.30 s, 1H), 5.81 (d, 1H), 4.00 (m, 1H), 3.78 (m, 1H), 2.18 (m, 1H), 2.07 (m, 1H), 1.67 (m, 4H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH3:12].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C1COCC1>[CH3:12][C:11]1[CH:10]=[C:9]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:20])[S:8][C:7]=1[CH3:6]
Reactant: Cc1ccsc1C
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2ccccc2)sc1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
n-Butyl lithium (19.6 ml, 49.1 mmol, 2.5 N in hexanes) was added dropwise to a stirred solution of 2,3- dimethyl-thiophene (5.0 g, 44.6 mmol) in THF (100 mL) at −78° C. under a dry nitrogen atmosphere. The solution was warmed to 0° C. for 30 min and recooled to −78° C. whereupon benzaldehyde (5.0 mL, 49.1 mmol) was added. After an additional 45 minutes, sat. aq. ammonium chloride was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated. The resultant oil was triturated with pet. ether to provide the title compound as a white solid (7.77 g, 80%): mp 80-81° C.: NMR (CDCl3); δ 7.45 (ddd, J=8, 1, 1 Hz, 2H), 7.37 (ddd, J=8, 8, 1 Hz, 2H), 7.3 (m, 1H), 6.57 (s, 1H), 6.93 (s, 1H, OH), 2.29 (s, 3H), 2.05 (s, 3H); MS (El) (M+) 218 (45%, MI): Anal. Calc. for C13H14OS: C, 71.52, H, 6.46, N, 0.00. Found: C, 71.41, H, 6.42, N, 0.09.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:27]OC(OC)N(C)C.CC(C)([O-])C.[K+].Cl>CC1CCCO1.C1COCC1>[N+:24]([C:8]1[CH:7]=[C:3]2[C:2]([CH:1]=[CH:27][NH:6][C:4]2=[O:5])=[CH:10][C:9]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:15][CH2:16]1)([O-:26])=[O:25]
Reactant: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(N)=O
Reactant: COC(OC)N(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(c2cc3cc[nH]c(=O)c3cc2[N+](=O)[O-])CC1
Temperature: 105 °C

Procedure:
A mixture of 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzamide (3.0 g, 8.46 mmol) and dimethylformamide dimethyl acetal (1.32 g, 11.08 mmol) in 2-methyl tetrahydrofuran (60 mL) were heated in a Dean stark apparatus at 105° C. for 30 min. The progress of the reaction was monitored by LCMS. The volume of the reaction was reduced to half and the reaction mass was cooled to 55° C. A solution of potassium tert-butoxide (1.44 g, 12.8 mL, 12.86 mmol) in THF (1 M) was added dropwise over a period of 30 min. The reaction mixture was allowed to heat at 65° C. overnight. After completion of the reaction, solvent was removed in vacuo, residue obtained was acidified with 1.5 N HCl. The aqueous layer was extracted in dichloromethane (5×75 mL). The combined extract was washed with water, brine solution and dried over anhydrous Na2SO4. The crude product obtained was purified by the flash column chromatography (230-400 size mesh) using 1.0-1.25% methanol in dichloromethane to afford the compound 7-nitro-6-(4-o-tolyl-piperazin-1-yl)-2H-isoquinolin-1-one. Yield (0.25 g, 8.3%; and reddish brown solid).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([N+:25]([O-])=O)[C:13]4[C:17]([CH:18]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Yield: 96.1 %

Procedure:
6-(1H-Indol-4-yl)-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (714 mg, 1.97 mmol) was dissolved in ethyl acetate (100 ml) and the compound was hydrogenated using the H-cube® (available from THALESNano) using 10% Pd/C catalyst at 30° C. and under 30 bar pressure of hydrogen. Solvent was removed in vacuo to give the title compound (629 mg) as an orange/brown solid.
Reaction SMILES: [CH:1]1([N:7]([CH3:24])[C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S([N:35]=[C:36]=[O:37])(C1C=CC(C)=CC=1)(=O)=O.[CH2:38](N)[CH3:39]>CN(C=O)C.C1COCC1>[CH:1]1([N:7]([CH3:24])[C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:36]([NH:35][CH2:38][CH3:39])=[O:37])[N:16]=[C:12]3[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CN(c1cc(-c2cccnc2)cc2nc(N)nn12)C1CCCCC1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N(C)C3CCCCC3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of Step 1 (290 mg, 0.90 mmol) was taken up in DMF (1 mL). TosNCO (0.44 g, 2.3 mmol) was added all at once. The solution became warm and was allowed to cool to room temperature over 1 h. Ethylamine (6 mL of a 2 M solution in THF) was added and the resulting mixture was microwaved at 100° C. for 10 min then at 120° C. for 30 min. The resulting solid was collected by filtration and triturated with CH2Cl2/MeOH to afford 1-[5-(cyclohexyl-methyl-amino)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-ethyl-urea. MS m/z 394 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[NH:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[NH:7][C:8](=[O:10])[CH3:9])=[O:3]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C(=O)CBr)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 110.0 g. (0.62 mole) of 3'-acetylacetanilide in 2400 ml. of chloroform is added dropwise a solution of 33.0 ml. (102.9 g; 0.644 mole) of bromine in 240 ml. of chloroform. The solution is stirred one hour and the resultant precipitate is then filtered, washed with ether and dried. The solid is stirred in a large volume of water to give an oily precipitate which crystallizes on further stirring. The solid is filtered, washed with water and then 2-propanol. The dried product weighs 148.34 g., and is recrystallized from 2-propanol to give the product, melting point 108.5°-110° C. Analysis: Calcd, for C10H10BrNO2 : Calcd: C, 46.90; H, 3.94; Br, 31.20; N, 5.47. Found: C, 47.12; H, 3.94; Br, 31.21; N, 5.47.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH2:30])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31]1([C@H:37]([NH:39][C:40]([NH2:42])=[O:41])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1>[NH2:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:42][C:40]([NH:39][C@@H:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:38])=[O:41])=[CH:3][C:4]=2[N:10]([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]=1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6-Chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (5C; 4.0 g, 9.73 mmol), (R)-1-(1-phenylethyl)urea (2.4 g, 14.60 mmol), cesium carbonate (7.9 g, 24.34 mmol) and BrettPhos pre-catalyst (467 mg, 0.584 mmol) were charged in a 350 mL pressure vessel with 1.4-dioxane (88 mL). The system was degassed and stirred at 100° C. for 8 h. The reaction mixture was filtered through Celite, evaporated in vacuo, dissolved in DCM, and purified by flash chromatography (0-20% EtOAc/DCM) to afford (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C34H30N6O2 [M+1]+ 539. found 539.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[F:49][C:50]([F:62])([F:61])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH2:57][C:58]([OH:60])=O>>[F:61][C:50]([F:49])([F:62])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH2:57][C:58]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:60]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)Cc2ccccc2C(F)(F)F)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2-trifluoromethylphenylacetic acid, mp 144°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=3)[N:5]=[CH:6][C:7]2=[O:13])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=c1cnc2cc(F)c(F)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Yield: 22.3 %

Procedure:
6,7-Difluoroquinoxalin-2(1H)-one (Intermediate 152, 1.0 g, 5.50 mmol) was deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (6.6 mmol) as described for Intermediate 2. Chromatography on silica gel with 5% toluene/ethyl acetate gave 500 mg (23%) of the product as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]4[CH2:24][CH2:23][O:22][CH2:21]4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[F:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]([O:32][CH3:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[O:22]1[CH2:23][CH2:24][C@@H:20]([O:19][C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][N:5]4[N:4]=[CH:3][C:2]([C:28]5[C:29]([O:32][CH3:33])=[N:30][CH:31]=[C:26]([F:25])[CH:27]=5)=[C:6]4[N:7]=3)[CH2:12][CH2:13]2)=[O:18])[CH2:21]1
Reactant: COc1ncc(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O[C@@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ncc(F)cc1-c1cnn2ccc(N3CCN(C(=O)O[C@@H]4CCOC4)CC3)nc12
Temperature: 25 °C
Yield: 27.1 %

Procedure:
(R)-tetrahydrofuran-3-yl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (100 mg, 0.25 mmol), 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (127 mg, 0.5 mmol), triethylamine (211 uL, 1.5 mmol), Pd(OAc)2 (1 mg, 0.0025 mmol), and x-Phos (5 mg, 0.005 mmol) were taken up in 4 mL dioxane and 1 mL water under nitrogen and stirred at 85° C. for 2 hours. Reaction then cooled to room temperature, filtered through celite plug with acetonitrile and DCM. Reduced in vacuo and purified on Shimadzu neutral phase prep, lypholized to get 30 mg product. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=7.83 Hz, 1H), 8.72 (dd, J=3.03, 10.36 Hz, 1H), 8.56 (s, 1H), 7.94 (d, J=3.03 Hz, 1H), 6.86 (d, J=7.83 Hz, 1H), 5.18 (d, J=1.77 Hz, 1H), 4.00 (s, 3H), 3.71-3.83 (m, 8H), 3.32 (s, 2H), 2.08 (s, 1H), 2.13 (s, 1H), 1.89-2.00 (m, 1H) LRMS (ESI) m/z 443 [(M+H)]+, calc'd for C21H23FN6O4: 442.45.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=1)=[O:19].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:15][C:16]2[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([C:28]([F:31])([F:29])[F:30])[CH:22]=2)=[O:19])=[CH:9][CH:8]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CNc2ccccc2C(=O)Nc2ccc(Br)c(C(F)(F)F)c2)cn1
Reaction time: 16 h

Procedure:
Sodium cyanoborohydride (8.80 g of 95%, 133 mmol) is added in portions over 30 minutes to a stirred mixture of acetic acid (3.8 mL), 6-methoxy-3-pyridinecarboxaldehyde (Fluka, Buchs, Switzerland; 7.80 g, 57 mmol) and 2-amino-N-(4-bromo-3-trifluoromethylphenyl)-benzamide (step 1.2; 13.65 g, 38 mmol) in methanol (380 mL) at 25° C. The mixture is stirred for 16 hours. The solvent is evaporated under reduced pressure to give a residue which is treated with a saturated aqueous solution of sodium hydrogen carbonate (500 mL) and extracted with dichloromethane (3×150 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product that is purified by column chromatography on silica gel, eluent 5% ethyl acetate in dichloromethane and recrystallised from diethylether-hexane to give the title compound as a beige crystalline solid, m.p. 101–103° C.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.Cl.[NH2:22][OH:23]>CO>[OH:23][NH:22][C:11]([C:8]1[CH:7]=[C:6]([CH3:13])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][N:9]=1)=[NH:12]
Reactant: Cc1cc(C#N)ncc1CC(C)C
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C(=N)NO)ncc1CC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 123 %

Procedure:
To a solution of 5-isobutyl-4-methyl-pyridine-2-carbonitrile (106 mg, 608 μmol) in methanol (3 mL), triethylamine (123 mg, 1.22 mmol) and hydroxylamine hydrochloride (63 mg, 913 μmol) is added. The mixture is stirred at 75° C. for 18 h before it is concentrated. The residue is dissolved in aq. NaHCO3 (pH 7-8) and extracted with DCM (6×50 mL). The org. extracts are combined, dried over MgSO4, filtered, concentrated and dried to give the title compound (155 mg) as a white solid; LC-MS: tR=0.67 min, [M+1]+=208.01; 1H NMR (CD3OD): δ0.97 (d, J=6.8 Hz, 6H), 1.84-1.96 (m, 1H), 2.37 (s, 3H), 2.58 (d, J=7.3 Hz, 2H), 7.67 (s, 1H), 8.26 (s, 1H).