Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:37])[C:19](=[O:36])[NH:20][N:21]=2)[C@@H:10]([CH3:38])[CH2:9]1)=O)(C)(C)C.[ClH:39]>>[ClH:39].[F:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([F:35])[C:28]=1[C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:36])[C@H:18]3[CH3:37])=[CH:15][C:14]=1[C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:38]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4F)c([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cc3N21
Agent: Cl
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4c(F)cccc4F)c([C@@H]4CCNC[C@@H]4C)cc3N21
Yield: 100 %

Procedure:
A solution of (3R,4R)-4-[(R)-7-(2,6-difluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.005 g, 0.01 mmol) in HCl (4M in EtOAc, 1 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give crude (R)-7-(2,6-difluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride (0.005 g, 100%), which was used directly in the next step without purification. LC/MS (Table 1, Method 25) Rt=0.717 min.; MS m/z: 427 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:4]=[C:3]1[CH3:23]>CO.[Pd]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:4]=[C:3]1[CH3:23]
Reactant: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)n1C
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(-c2cc(Oc3ccc(N)nc3)ccn2)n1C
Yield: 69.2 %

Procedure:
A solution of 2-(1,2-dimethyl-1H-imidazol-5-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (0.08 g, 0.257 mmol) in MeOH (20 mL) was treated with 10% Pd/C (50% w/w water, 2.73 mg, 0.001 mmol) and hydrogenated (1 atm) overnight. The solids were removed via filtration through diatomaceous earth, washed with warm MeOH and the filtrate concentrated to dryness to afford 5-((2-(1,2-dimethyl-1H-imidazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (50 mg, 69%). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J=5.8 Hz, 1H), 7.81 (d, J=2.9 Hz, 1H), 7.29 (dd, J=8.9, 3.0 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J=2.4 Hz, 1H), 6.66 (dd, J=5.7, 2.5 Hz, 1H), 6.51 (d, J=8.9 Hz, 1H), 6.02 (s, 2H), 3.80 (s, 3H), 2.32 (s, 3H); MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: C1CCNC1
Solvent: ClCCl
Product: Cc1cc(O)cc(C)c1CN1CCCC1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
To a stirring solution of 2,6-dimethyl-4-hydroxybenzaldehyde (8.2 g, 52.1 mmol) in methylene chloride (80 mL) at 0 C (ice/water bath) was added pyrrolidine (6.5 mL, 78.1 mmol) followed by Na(Oac)3BH and then the reaction was warmed to rt. After 2 hr the reaction was quenched with 1 N NaOH and extracted with methylene chloride. The combined organic layers were dried over MgSO4, filtered and concentrated. This material was triterated with diethyl ether and filtered. The filtrate was concentrated and chromatographed by flash column chromatography using a 330 g ISCO column, eluting with a gradient of 10%, 20%, 30%, 50% MeOH/CHCl3. The product containing fractions were collected and concentrated to give the title compound (3.5 g, 33% yield) as a yellow solid. LCMS-data: 392.2, and 206.3 (M+H)+ (calculated for C13H19NO 205.3). 1H NMR data (CDCl3): 7.52 (bs, 1H), 6.17 (s, 2H), 3.57 (s, 2H), 2.67-2.61 (m, 4H), 2.25 (s, 6H), 1.82-1.72 (m, 4H); C13 NMR δ 155.2, 139.0, 127.4, 116.2, 54.8, 53.0, 23.4, 20.5.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]([C:22]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([CH3:32])[CH:25]=3)=[O:23])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].N>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:29][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:22]([N:14]2[CH2:13][CH2:12][C:11]3[N:10]=[C:9]([CH3:33])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:17]=3[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=3)=[O:23])=[CH:25][C:26]=1[CH3:32]
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1C#N
Agent: Cl[Co]Cl
Agent: N
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CN
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A solution of 4-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzonitrile from Example E121.1 (830 mg, 1.9 mmol) in methanol (10 ml) at room temperature was treated with cobalt(II) chloride hexahydrate (913 mg, 3.8 mmol). The mixture was stirred for 15 min then cooled down to 0° C. Sodium borohydride (726 mg, 19 mmol) was added portion-wise and the reaction mixture was stirred for 2 h at room temperature. 35% Ammonia (5 ml) was added dropwise and the mixture was stirred for 30 min then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (680 mg, 81%).
Reaction SMILES: Br[C:2]1[C:26]([F:27])=[C:25]([NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]2[C:6](=[O:24])[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([F:23])[CH:11]=3)[O:9][C:4]=2[C:3]=1[F:35].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.O>CS(C)=O>[F:27][C:26]1[C:2]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[C:3]([F:35])[C:4]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])=[C:12]([F:23])[CH:11]=3)=[CH:7][C:6](=[O:24])[C:5]=2[C:25]=1[NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(Br)c(F)c3o2)cc1F
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2c(F)c(NC(=O)C(C)(C)C)c3c(=O)cc(-c4ccc(NC(=O)C(C)(C)C)c(F)c4)oc3c2F)CC1
Temperature: 100 °C
Reaction time: 7 h
Yield: 58.2 %

Procedure:
580 mg (1.05 mmol) of 7-bromo-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 84 (2) was dissolved in 6 mL of dimethyl sulfoxide, 1.2 mL (10.5 mmol) of N-methylpiperazine was added and the mixture was stirred at 100° C. for 7 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 350 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-(4-methylpiperazin-1-yl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 58%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:25][CH2:21][CH:22]([CH3:24])[CH3:23])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CC(C)CN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)C)c1C
Yield: 55.3 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (40.0 g, 181 mmol), triethylamine (26.5 mL, 190 mmol), and isobutyl amine (18.9 mL, 190 mmol) in N,N-dimethylformamide (500 mL) was stirred at room temperature over night. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and washed with water (3×80 mL) and brine (40 mL). The aqueous was extracted with ethyl acetate (3×50 mL) and the back-extracts washed with water (3×40 mL) and brine (30 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC eluting with a gradient of 10-30% ethyl acetate in hexanes to give 25.8 g of 2-chloro-N-isobutyl-5,6-dimethyl-3-nitropyridin-4-amine as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH:15]=O.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH:8]=[CH:15][C:14]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:12]([O:11][CH3:10])[CH:13]=2)[O:3]1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C=CC2=CC(=O)C(C)(C)O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.9 %

Procedure:
To a mixture of 2,2,5-trimethyl-3(2H)-furanone (2.5 g, 19.8 mM) and 3,4,5-trimethoxybenzaldehyde (4.7 g, 23.8 mM) in ethanol was added 1N aqueous sodium hydroxide (4 mL, 4mM). After the reaction mixture was stirred for 48 hours at room temperature, the solution was concentrated to 50 mL and diluted with water (300 mL). The aqueous layer was extracted with diethyl ether (4×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a dark yellow crystalline solid. The crude product was purified by chromatography (silica gel, petroleum ether-ethyl acetate) to give light yellow crystals (5.0 g, 83% yield), m.p. 149°-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:15]1([CH2:14][CH2:13][N:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)N1CCN(CCN2CCCCC2)CC1

Procedure:
A mixture of 1-ethoxycarbonylpiperazine (10.9 grams; 0.069 moles), N-(2-chloroethyl)piperidine (10.2 grams; 0.069 moles) and potassium carbonate, (9.5 grams; 0.069 moles) in 100 cc of ethanol is heated to reflux for 4 hours. After cooling, the salt is filtered, the filtrate is evaporated and the oily residue is distilled under vacuo; b.p. 133°-136° C. (0.02 mm). Dihydrochloride: m.p. 254°-256° C. (from methanol); Rf=0.74 (MeOH-concentrated NH4OH 9.5:0.5); IR (neat); 2940, 2860, 2820, 1710, 1470, 1435, 1305, 1290, 1240, 1135, 1120, 1005, 770 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH:12]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2=CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
4-(6-Methoxy-pyridin-3-yl)-cyclohex-3-enone (as prepared in Step C, 1.02 g, 5.02 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide HCl salt (as prepared in the previous step, 2.54 g, 7.53 mmol) in DCM (15 mL) was treated with TEA (2.80 mL, 20 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 3.20 g, 15 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solids.
Reaction SMILES: O1CCOCC1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C(O)=O.C(=O)([O-])OC[CH2:29]/[CH:30]=[C:31](/[CH2:33][CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])\[CH3:32]>CCCCC>[CH3:32][C@@H:31]([CH2:33][CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[CH:30]=[CH2:29]
Reactant: CC(C)=CCC/C(C)=C/CCOC(=O)[O-]
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCCCC
Solvent: O=CO
Solvent: C1COCCO1
Product: C=C[C@@H](C)CCC=C(C)C
Temperature: 20 °C
Reaction time: 17 h
Yield: 100.4 %

Procedure:
In a Schlenk's tube, (R)-(+)-3-diphenylphosphino-3'-methoxy-4,4'-biphenanthryl prepared in Example 1 (6.24 mg, 0.011 mmol) and tris(dibenzylideneacetone)(chloroform)dipalladium (0) (2.6 mg, 0.0025 mmol) were charged, and dioxane was added under a nitrogen atmosphere. To the mixture cooled on an ice bath, 1,8-bis(dimethylamino)naphthalene (128.6 mg, 0.60 mmol) and formic acid (52.5 mg, 1.14 mmol) were added in this order. At the same temperature, geranylmethyl carbonate (104.5 mg, 0.49 mmol) was added, and the mixture was stirred at 20° C. for 17 hours. The reaction mixture was diluted with pentane and washed with water, and the organic layer was dried over anhydrous magnesium sulfate and filtrated through a mass of silica gel. From the filtrate, the solvent was evaporated off under reduced pressure to obtain (S)-3,7-dimethyl-1,6-octadiene as a colorless oil (68.0 mg). Yield, >99%. Rotatory power: :[α]D20 =+8.1 (C=1.6, CHCl3). 1 H-NMR (CDCl3): δ(ppm)=0.98 (d, J=7.0 Hz, 3H), 1.27-1.36 (m, 2H), 1.60 (s, 3H), 1.67 (s, 3H), 1.96 (q, J=7.0 Hz, 2H), 2.12 (heptet, J=7 Hz, 1H), 4.88-4.99 (m, 2H), 5.05-5.15 (m, 1H), 5.70 (ddd, J=17.1, 10.1 and 7.0 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][N:5]1[C:13]2[CH2:12][C:11]([CH3:15])([CH3:14])[CH:10]([CH:16]=O)[C:9](=O)[C:8]=2[CH:7]=[N:6]1>CO>[CH3:1][N:2]1[CH:16]=[C:10]2[C:11]([CH3:15])([CH3:14])[CH2:12][C:13]3[N:5]([CH3:4])[N:6]=[CH:7][C:8]=3[C:9]2=[N:3]1
Reactant: Cn1ncc2c1CC(C)(C)C(C=O)C2=O
Reactant: CNN
Solvent: CO
Product: Cn1cc2c(n1)-c1cnn(C)c1CC2(C)C
Temperature: 0 °C

Procedure:
A solution of 0.59 ml of methylhydrazine in 20 ml of methanol was added dropwise to an ice-cold solution of 2.2 g of 4,5,6,7-tetrahydro-1,6,6-trimethyl-4-oxo-1H-indazole-5-carboxaldehyde in 80 ml of methanol. The solution was heated at reflux for 45 minutes and the solvent was removed under reduced pressure. The residue was dissolved in hot toluene and cooled to provide off-white crystals which were recrystallized from toluene to give 2,4,5,6-tetrahydro-2,4,4,6-tetramethylbenzo[1,2-c:3,4-c']dipyrazole melting at about 172°-173° C. The initial toluene mother liquor was concentrated under reduced pressure to provide tan crystals which were recrystallized from toluene to give 1,4,5,6-tetrahydro-1,4,4,6-tetramethylbenzo[1,2-c:3,4-c']dipyrazole melting at about 105°-108° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][N:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([NH:22][C:23]3[NH:27][N:26]=[CH:25][CH:24]=3)[N:16]=2)[CH2:12][C@@H:11]([C:28]([O:30]C)=[O:29])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH4+].[Cl-]>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][N:13]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([NH:22][C:23]3[NH:27][N:26]=[CH:25][CH:24]=3)[N:16]=2)[CH2:12][C@@H:11]([C:28]([OH:30])=[O:29])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(c2cc(C)cc(Nc3ccn[nH]3)n2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2ccn[nH]2)nc(N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](C(=O)O)C2)c1
Reaction time: 4 h
Yield: 17.1 %

Procedure:
To the solution of methyl cis-5-[(tert-butoxycarbonyl)amino]-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyridin-2-yl]piperidine-3-carboxylate (11.0 mg) in MeOH (5 ml) was added 5 M aqueous solution of NaOH (468.0 μl) at room temperature. After stirring for 4 hours, NH4Cl was added for neutralization and the mixture was concentrated. The residue was suspended into the mixed solvent of CHCl3 and MeOH. The insoluble material was removed by filtration. The filtrate was concentrated and the residue was purified with preparative RP-HPLC. The desired fraction was neutralized by addition of aqueous solution of NH3 and concentrated. And the residue was purified again with preparative RP-HPLC (mobile phase: H2O and acetonitlile, without TFA) to give cis-5-[(tert-butoxycarbonyl)amino]-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyridin-2-yl]piperidine-3-carboxylic acid (1.82 mg) as colorless solid.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2[nH]ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine 7-oxide was added slowly to 200 mL POCl3 and the resulting mixture stirred at 80° C. overnight. The excess POCl3 was then removed in vacuo and the residue treated with 500 mL H2O and basified with saturated K2CO3 (aq), prior to extraction with EtOAc (2×300 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 76%). MS (ES+): 153 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:25]3[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23][CH2:24]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
To tert-butyl 4-hydroxypiperidine-1-carboxylate (402 mg, 2.0 mmol) in methylene chloride (20 mL) and triethylamine (303 mg, 3.0 mmol) at 4° C. was added methanesulfonyl chloride (274 mg, 2.4 mmol) drop-wise. The reaction was brought to ambient temperature and was stirred for 1 hour. The reaction mixture was concentrated in vacuo and diluted in diethyl ether (20 mL). The solution was washed with 1N hydrochloric acid (3 mL), water (3 mL), and saturated sodium bicarbonate (3 mL). The organics were dried (sodium sulfate) and concentrated in vacuo to afford tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate in quantitative yield. The product was used directly in the next step without further purification. A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (427 mg, 2.2 mmol), tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate (2.0 mmol), and cesium carbonate (847 mg, 2.6 mmol) in DMF (5 mL) was stirred at 100° C. overnight. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated to provide crude pale yellow oil 884 mg. MS (m/z): 378 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](O)=[CH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[NH2:17][NH2:18]>CCO>[C:7]1([C:6]2[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[NH:18][N:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(O)=CC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To a solution of 2-hydroxy-4-oxo-4-phenyl-but-2-enoic acid methyl ester (12.0 g, 58.2 mmol) in EtOH (30 ml) was added hydrazine monohydrate (2.84 mL, 58.2 mmol) and the mixture was heated at reflux for 5 h. The reaction mixture was cooled to room temperature and filtered in vacuo. The precipitate was washed with EtOH to give the desired product (6.02 g, 51.5% yield): MS (EI) for C11H10N2O2: 203.08 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:28]=[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([NH:20][CH2:21][CH:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[N:14]4[N:13]=3)=[CH:8][CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.BrC1C=C2C(C(C)=NN2S(C2C=CC(C)=CC=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:28]=[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([NH:20][CH2:21][CH:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[N:14]4[N:13]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc(Nc4nc5cccc(NCC6CCOCC6)n5n4)cc32)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc(Br)cc32)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c2cc(Nc3nc4cccc(NCC5CCOCC5)n4n3)ccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
N2-(3-Methyl-1-tosyl-1H-indazol-6-yl)-N5-((tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine. A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.074 g, 0.081 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.094 g, 0.162 mmol) in 1,4-dioxane (4 mL) was heated briefly with a heat gun until most of the solids had dissolved and then added to 6-bromo-3-methyl-1-tosyl-1H-indazole (0.295 g, 0.809 mmol), N5-((tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[1,5-c]pyridine-2,5-diamine (0.200 g, 0.809 mmol), and finely ground cesium carbonate (1.080 g, 3.32 mmol) in a sealable vessel with a stirbar. Nitrogen was blown in to blow out air. The resulting mixture was sealed, stirred vigorously, and heated at 100° C. for 3.5 h. The resulting green mixture was cooled to room temperature. Water (10 mL) was added with vigorous stirring. Solids were collected by vacuum filtration and washed thoroughly with water. The solids were taken up in dimethyl sulfoxide and methanol. The resulting mixture was heated with a heat gun and then quickly filtered. The filtrate was capped and let stand at room temperature for 30 min. Solids were collected by vacuum filtration, washed with methanol and diethyl ether, and dried under high vacuum at 40° C. to give the desired product (0.345 g, 0.649 mmol, 80% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.12 (s, 1H), 8.95 (d, J=1.17 Hz, 1H), 7.78 (d, J=8.20 Hz, 2H), 7.60-7.67 (m, 1H), 7.53-7.60 (m, 1H), 7.49 (t, J=8.20 Hz, 1H), 7.38 (d, J=8.59 Hz, 2H), 6.82 (d, J=8.59 Hz, 1H), 6.20-6.31 (m, 2H), 3.76 (dd, J=3.32, 11.13 Hz, 2H), 3.29 (t, J=6.25 Hz, 2H), 3.18 (t, J=10.93 Hz, 2H), 2.41 (s, 3H), 2.31 (s, 3H), 1.87-2.03 (m, J=4.30, 7.36, 7.36, 7.36, 7.36, 11.16 Hz, 1H), 1.73 (d, J=12.49 Hz, 2H), 1.28 (qd, 2H); MS (ESI) m/z 532.2 [M+1]+.