Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[C@@H:4]([NH:12]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C1COCC1.CNC>CO>[NH2:12][C@@H:4]([CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:3]([N:2]([CH3:31])[CH3:1])=[O:30]
Reactant: CN(C)C(=O)[C@H](Cc1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CNC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)[C@@H](N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 1.67 g of the compound obtained in Step 85-1 in a mixed solution of MeOH and THF (25 ml 4:1; v/v) was added a solution of 2 mol/L dimethylamine in MeOH (6.0 ml) and the reaction solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under vacuum, the obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 5/1; v/v, 0.1% NH4OH content) to obtain 0.66 g of the title compound (brown oil).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[F:12].CCN(C(C)C)C(C)C.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:5]3[CH:4]=[C:3]([F:12])[C:2]([F:1])=[CH:7][C:6]=3[N+:8]([O-:10])=[O:9])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(F)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 17.8 %

Procedure:
To a solution of 1,2,4-trifluoro-5-nitrobenzene (3.0 g, 18 mmol) and DIEA (4.2 ml, 24 mmol) in dry THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16 mmol) in THF (5 ml) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 20 hrs. It was then heated to 40° C. for 40 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=5:2). Recrystallization from EtOAc (10 ml) and hexanes (˜100 ml) gave the title compound as red crystals (0.8 g, 18%). NMR (400 MHz) 12.36 (s, 1H), 9.79 (s, 1H), 8.27 (m, 2H), 5.93 (s, 1H), 1.90 (m, 1H), 0.93 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 280; Found: [M+H]+ 281.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=O.[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:16].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:14]/[C:15]([C:17]2[CH:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCOc1ccc(C=O)cc1O
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1O
Yield: 132.1 %

Procedure:
A mixture of 3-hydroxy-4-propoxybenzaldehyde (0.4 g, 2.1 mmol), 3,5-dimethoxyacetophenone (0.371 mg, 2.1 mmol) and 50% w/v of aqueous sodium hydroxide (3.3 ml, 0.206 mol) in methanol (10 ml) at room temperature for 18 h. The yellow solid that precipitated was filtered and sequentially washed with cold methanol and ether and finally dried in a vacuum dessicator. Purification was achieved using column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) which gave 0.95 g (19%) of a yellow solid. 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.3 (m, 2H), 7.1 (d, 3H), 6.8 (d, 1H), 6.6 (d, 1H), 5.7 (s, 1H), 4.1 (t, 2H), 3.9 (s, 6H), 1.9 (m, 2H), 1.0 (t, 3H). 13C-NMR (CDCl3) δ 160.9, 146.0, 144.9, 128.4, 122.6, 120.2, 112.9, 106.2, 104.9, 70.6, 55.6, 22.4, 10.4. Mass Spectrum m/e (M+1) 343. Anal. Calcd. for C20H22O5: C, 70.16; H, 6.48. Found C, 70.08; H, 6.38.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:35](=O)[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])[NH:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([S:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])[NH:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: CCCCCCCN(CCCCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1)C(=O)Cc1ccc(F)cc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCCCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1)CCc1ccc(F)cc1F
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a solution of lithium aluminium hydride (1N in tetrahydrofuran, 2 mL) in dry tetrahydrofuran (30 mL), a solution of N-[5-[4,5-bis (4-methoxyphenyl)-1H-imidazol-2-ylthio]pentyl]-2,4-difluoro-N-heptylbenzeneacetamide (0.70 g, 0.00107 mol) in dry tetrahydrofuran (15 mL) was added slowly. The reaction mixture was heated to reflux for 5 hours and was then allowed to cool to ambient temperature. The reaction mixture was poured into a mixture of 10% aqueous sodium sulfate (150 mL) and ice (150 mL). The resultant emulsion was filtered through Celite® and the filtrate was extracted with ethyl acetate (3×100 mL). The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo to give a crude oil. The product was purified by flash chromatography on silica gel (100 mL) eluting methanol: methylene chloride (5:95 v:v) to give the title compound as a viscous colorless oil (0.46 g, 0.000723 mol). 1H NMR (CDCl3) δ 9.2-9.15(bs,1H), 7.56-7.25(m,4H), 7.11(m,1H), 6.94-6.70(m,6H), 3.81(m,6H), 3.07(t,2H), 2.74-2.58(m,4H), 2.43(m,4H), 1.71(m,2H), 1.53-1.20(m,14H), 0.91(t,3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16]1[NH:17][C:18]([Br:21])=[CH:19][N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[Br:21][C:18]1[NH:17][C:16]([C@@H:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1ncc(Br)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@@H](Cc1ccccc1)c1ncc(Br)[nH]1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
[(S)-1-(5-bromo-1H-imidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester: To a solution of 92D (30 g) in anisole (100 mL) was added TFA (250 mL) and the reaction was stirred at 100° C. for 18 h. The reaction mixture was evaporated completely, basified with 5% NaOH solution and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Recrystallization from hexane gave (S)-1-(5-bromo-1H-imidazol-2-yl)-2-phenyl-ethylamine as a white solid 6 (11 g, 67%). 1HNMR (CD3OD, 400 MHz), δ 7.26 (m, 3H), 7.06 (d, 2H), 6.96 (s, 1H), 4.18 (m, 1H), 3.09 (m, 2H). LCMS m/z 266 (M+H)+. To this intermediate (10 g, 37 mmol) in chloroform (250 mL) was added Boc anhydride (8.6 g, 39 mmol) dropwise at −15° C. over a period of 30 min. The reaction was warmed to 15° C. and stirred at the same temperature for 8 h. The reaction mixture was diluted with chloroform, washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by recrystallisation from hexane to give 92E as an off-white solid (12.5 g, 91%). 1HNMR (CDCl3, 400 MHz), δ: 10.2 (bs, 1H), 7.3 (m, 5H), 7.15 (d, 2H), 6.85 (s, 1H), 5.34 (bs, 1H), 4.84 (m, 1H), 3.28 (dd, 2H), 1.38 (s, 9H). LCMS m/z 366 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[C:28]([CH3:37])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[CH:6]=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:36])[N:33]([CH3:34])[CH3:35])=[C:28]([CH3:37])[N:27]=2)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=1
Reactant: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)ccc1C(=O)N(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)ccc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {(1S,2R)-2-[(6-carbamoyl-5-{[5-(dimethylcarbamoyl)-6-methylpyridin-2-yl]amino}pyridin-3-yl)amino]cyclohexyl}carbamate (48 mg, 0.094 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.10 mL, 1.3 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[5-(dimethylcarbamoyl)-6-methylpyridin-2-yl]amino}pyridine-2-carboxamide. MS ESI calc'd. for C21H30N7O2 [M+H]+ 412. found 412. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.55 (d, J=2.3 Hz, 1H), 7.91 (s, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.45 (d, J=. 8.4 Hz, 1H), 7.33 (s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.62 (d, J=7.0 Hz, 1), 3.63-3.50 (m, 1H), 3.37-3.27 (m, 1H), 2.99 (s, 3H), 2.82 (s, 3H), 2.34 (s, 3H), 1.88-1.72 (m, 2H), 1.69-1.50 (m, 4H), 1.48-1.31 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[C:21]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>CC#N>[Cl:19][C:20]1[C:21]([N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:2]3[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:34][CH2:35]2)=[N:22][CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=1
Reactant: NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(NC2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 92.9 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.106 g, 1.050 mmol) and 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (0.294 g, 1.050 mmol) in MeCN (mL) was heated in a microwave reactor at 120° C. for 30 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 1:1 mixture of heptane and EtOAc as eluant, to give the title compound (0.344 g, 93%); 1H NMR (500 MHz, CDCl3): δ 8.34-8.33 (m, 1H), 7.74-7.72 (m, 1H), 7.57-7.54 (m, 2H), 7.49-7.46 (m, 3H), 5.27 (d, 1H), 4.47-4.39 (m, 1H), 3.85-3.78 (m, 2H), 3.24-3.14 (m 1H), 2.55-2.48 (m 2H), 1.82-1.76 (m 2H), 1.60 (d 6H), 1.56-1.48 (m 2H); 13C NMR (125 MHz, CDCl3): δ 160.0, 158.7, 143.1, 136.2, 134.5, 131.8, 130.2, 129.0, 125.3, 121.3, 120.6, 120.3, 107.1, 66.1, 50.3, 47.9, 47.4, 32.4, 20.4; Mass Spectrum: M−H+ 529.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21](Cl)[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH:18]=[N:17][C:16]=2[CH:27]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[C:18]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([F:2])=[CH:4][CH:5]=3)=[N:17][C:16]=2[CH:27]=1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Reactant: Fc1ccc(C[Zn+])cc1
Agent: [Cl-]
Product: Fc1ccc(CC2=Nc3cc(Cl)ccc3Nc3ccccc32)cc1
Yield: 77.2 %

Procedure:
4-Fluorobenzylzinc chloride (0.8 ml, 0.5 M in THF, 0.4 mmol) and 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (53 mg, 0.2 mmol) were reacted according GP10 to give 52 mg of the title compound (160FE59). MS (ESI) 337 (MH+). Purity for MH+ (UV/MS) 90/90.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[CH3:22])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:23]1([N:19]2[CH2:20][CH2:21][N:16]([C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)=[O:15])[C@@H:17]([CH3:22])[CH2:18]2)[CH2:26][CH2:25][CH2:24]1
Reactant: C[C@H]1CNCCN1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2CCC2)CCN1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1-[1-(tert-Butoxycarbonyl)-piperidine-4-carbonyl]-2-methylpiperazine (D21)(0.13 g) and cyclobutanone (0.1 ml) were stirred in methanol (10 ml) at rt for 10 min and then sodium triacetoxyborohydride (0.26 g) was added and the reaction stirred at rt overnight. The reaction mixture was evaporated to a minimum and then redissolved in DCM (30 ml), and washed with saturated potassium carbonate solution (3×25 ml). The organic layer was dried (MgSO4) and evaporated to give the title compound (D24) as a clear oil (0.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([CH:26]4[CH2:28][CH2:27]4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[F:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N:21]([C:19]2[C:18]([CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:11]3[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:20]=2)[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:39][C:38]=1[F:46])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12

Procedure:
A mixture of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.0 g, 4.77 mmol), (4-(benzyloxy)-3-fluorophenyl)boronic acid (1.762 g, 7.16 mmol), Cu(OAc)2 (1.301 g, 7.16 mmol), triethylamine (3.33 mL, 23.87 mmol) and powdered 3 Å molecular sieves (2 g) in CH2Cl2 (60 mL) was stirred in a flask open to the air and equipped with a drying tube. After 12 hours the mixture was treated with additional (4-(benzyloxy)-3-fluorophenyl)boronic acid (1.762 g, 7.16 mmol) and Cu(OAc)2 (1.301 g, 7.16 mmol) and stirred at room temperature for 4 d. The mixture was diluted with CH2Cl2, filtered through Celite and the dark brown filtrate was concentrated to dryness. The crude material was purified by flash chromatography on silica gel (0-4% EtOAc/CH2Cl2) to afford the desired compound which was further purified by flash chromatography on silica gel eluted (0-40% EtOAc/hexane) to give the desired compound as a light-tan solid (406 mg, 14%). LCMS (m/z, ES+)=619 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH2:11][O:10][CH2:9][CH2:8][C:6]=2[N:7]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:5]2[CH2:11][O:10][CH2:9][CH2:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c2c(n1)CCOC2
Product: Nc1nc(Cl)c2c(n1)CCOC2
Yield: 22 %

Procedure:
By reacting 2-amino-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-4-ol (562 mg, 3.36 mmol) and phosphorous oxychloride (3 ml), there was obtained the object compound (136 mg, 22%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:22][C:21]=2[CH:20]=[C:19](O)[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:22][C:21]=2[CH:20]=[C:19]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1c2ccccc2oc2cc(OS(=O)(=O)C(F)(F)F)cc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.54 mL, 3.21 mmol) was added slowly to a solution of, 1,3-dihydroxyxanthen-9-one (689 mg, 3.02 mmol) and pyridine (7.3 mL) in CH2Cl2 (30 mL) at 0° C. The reaction then was allowed to slowly warm to RT and stirred for 16 h. The orange mixture then was dissolved in CH2Cl2 (100 mL), and washed with 10% citric acid (2×25 mL) and brine (1×25 mL). The organics were dried (Na2SO4), concentrated, and purified by Biotage chromatography using 10% EtOAc/hexanes as eluent to yield 702 mg (65%) of trifluoromethanesulfonic acid 1-hydroxy-9-oxo-9H-xanthen-3-yl ester as a light yellow solid. Rf=0.65 (50% EtOAc/hexanes). See R. Pillai et al., J. Org. Chem., 51, pages 717-723 (1986). 1H NMR (DMSO-d6, 400 MHz) δ: 12.90 (s, 1H), 8.20 (d, 1H), 7.96 (dd, 1H), 7.70 (d, 1H), 7.56 (dd, 1H), 7.37 (m, 1H), 7.05 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20](O)=[O:21])=[CH:16][C:11]2=[N:10][N:9]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:39]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])(=[O:42])[NH:40][NH2:41]>C1COCC1>[C:39]([NH:40][NH:41][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:17]([C:15]2[CH:14]=[CH:13][N:12]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:9][N:10]=[C:11]3[CH:16]=2)[CH:18]=1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1ccc(C(=O)O)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Temperature: 50 °C

Procedure:
To a solution of 3-(3-(2-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzoic acid (444 mg, 1.22 mmol) in 15 mL of THF at RT was added CDI (218 mg, 1.34 mmol). The resulting mixture was heated for 1 h at 50° C. The reaction mixture was then cooled to RT and tert-butyl carbazate (177 mg, 1.34 mmol) was added. The reaction mixture was again heated at 50° C. for 24 h. After the reaction mixture was concentrated to dryness, the residue was purified on the ISCO (40 g column, 50-100% EtOAc in Hexanes) to afford the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 478.1 (M+1).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S@@:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.[CH3:11][C@H:12]([C@H:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=O>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:11][C@H:12]([C@H:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:13]=[N:9][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:8]
Reactant: CCC[C@@H](C)[C@@H](C)C=O
Reactant: Cc1ccc([S@@](N)=O)cc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)C=NS(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
Titanium(IV)ethoxide (5.16 g, 22.6 mmol) and (S)-(+)-p-toluenesulfinamide(7.02 g, 45.2 mmol) were added to (2R,3R)-2,3-dimethyl-hexanal (2.9 g, 22.6 mmol) in dry THF (30 mL). The resulting mixture was stirred at room temperature for 18 hours and poured into a brine solution (40 mL). The slurry was rapidly stirred for 10 minutes and filtered. The filtrate was extracted into ethyl acetate, washed with brine and dried over MgSO4. The solvent was evaporated and the residue was filtered through a silica plug, eluting with 50/50 solution of hexane/ethyl acetate to afford the titled compound (3.1 g, 51.6% yield) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (m, 6 H) 1.1 (m, 4 H) 1.3 (m, 3 H) 1.7 (m, 1 H) 2.4 (s, 3 H) 2.5 (m, 1 H) 7.3 (d, J=8.3 Hz, 2 H) 7.5 (d, J=8.1 Hz, 2 H) 8.1 (d, J=5.4 Hz, 1 H). MS, m/z (relative intensity): 266 [M+1H, 100%].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([OH:6])=[CH:4][C:3]=1[OH:10].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:6][C:5]1[C:7]([Cl:9])=[CH:8][C:2]([Cl:1])=[C:3]([OH:10])[CH:4]=1)[CH:12]=[CH2:11]
Reactant: Oc1cc(O)c(Cl)cc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
4,6-dichlororesorcinol (3.80 g, 21 mmol), allyl bromide (1.82 mL, 21 mmol) and potassium carbonate (2.24 g, 21 mmol) were combined in DMF and stirred at room temperature for 18 hours. The DMF was removed in vacuo and the residue acidified with 2M hydrochloric acid (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic solution was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate 9:1 to 4:1 to afford the title compound as a yellow oil in 27% yield, 1.24 g.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: N#CC1(CNc2cccc(Br)n2)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: N#CC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A mixture of 4-((6-bromopyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate S, 410 mg, 1.384 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (362.2 mg, 2.07 mmol), PdCl2(dppf).CH2Cl2 adduct (113 mg, 0.14 mmol), DME (5 Ml) and 2 M aqueous Na2CO2 (1.75 Ml, 3.5 mmol) was sealed and stirred at 110° C. for 20 min using microwave reactor. After cooling to room temperature the mixture was extracted with EtOAc (35 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 24 g, EtOAc/hexane=5/100 to 50/50] to provide 4-((5′-chloro-2′-fluoro-2,4′-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (360 mg, 75% yield). LCMS (m/z): 347 [M+H]+; retention time=0.814 min.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=5)=[CH:22][CH:21]=4)[CH2:19][CH2:18][CH2:17]3)[N:12]=2)[CH:8]=[N:7]1)C.C1COCC1.O.[OH-].[Li+].Cl>O.CO>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:16]3([C:13]4[N:12]=[C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]([OH:33])=[O:3])[CH:10]=5)[O:15][N:14]=4)[CH2:19][CH2:18][CH2:17]3)=[CH:21][CH:22]=2)=[CH:27][N:28]=1
Reactant: CCOC(=O)Cn1cc(-c2nc(C3(c4ccc(-c5cnc(N)nc5)cc4)CCC3)no2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(-c2ccc(C3(c4noc(-c5cnn(CC(=O)O)c5)n4)CCC3)cc2)cn1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
R102 (784 mg, 1.76 mmol) is treated with THF (7.0 mL), methanol (1.5 mL), water (3.0 mL), and lithium hydroxide monohydrate (222 mg, 5.28 mmol) and the resulting mixture is stirred at 40° C. for 1.5 hours. The mixture is then treated with 1N hydrochloric acid (5.28 mL, 5.28 mmol) and concentrated in vacuo to afford R103 (960 mg).