Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[P].FF>>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: FF
Agent: [P]
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Yield: 70 %

Procedure:
Then, the first distillation of Example 1 was repeated, thereby to obtain 363.8 kg of trifluoromethanesulfonic acid anhydride which is colorless and transparent. By chemical analysis, this first distillate was found to have a purity of 97 wt % and contain 2 wt % of trifluoromethanesulfonic acid ester, 1 wt % of trifluoromethanesulfonic acid, up to 5 wt ppm of phosphorus, and 2,440 wt ppm of free fluorine. The actual amount of trifluoromethanesulfonic acid anhydride produced by the reaction was 32.9 kg, and the yield was 70%, based on the amount of trifluoromethanesulfonic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:5]([Br:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:26][NH2:27]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:27][NH:26][C:13](=[O:14])[C:6]=2[C:5]([Br:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(Br)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccccc2)nc(Br)c2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of 1 ml of ethanol and 2 ml of hydrazine monohydrate was dissolved 90 mg of 3-amino-6-bromo-4,5-diethoxycarbonyl-2-phenylpyridine, and the mixture was stirred for 2 hours at room temperature. After the solvent was distilled off, the resulting crystals were collected by filtration with ethanol. Water was added to the crystals, and the mixture was neutralized with 1N hydrochloric acid, the resulting crystals were collected by filtration. The crystals were dissolved in a small volume of methanol. After mixing the methanol solution with silica gel, purification by silica gel column chromatography (eluent:ethyl acetate→ethylacetate/methanol 1:1) was conducted, followed by collection by filtration.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]([O:19][CH2:21][C:22](=[O:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Product: O=C(C[C@@H]1CCCN1C(=O)OCc1ccccc1)OCC(=O)c1ccccc1
Yield: 48.3 %

Procedure:
The title compound (0.700 g) was prepared from (S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid benzyl ester (1.00 g, Aoyama et al, Chem. Pharm. Bull., 3249, 29,11,1981) and 2-bromoacetophenone (0.760 g) according to the method of description 36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])C2C=CC=CC=2)=[N:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:15][C:17]2[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=2)=[N:6][CH:7]=1
Reactant: OC(c1ccccc1)c1ccc(Cl)cn1
Reactant: [O-][n+]1ccc(Cl)cc1
Product: [O-][n+]1ccc(OCc2ccc(Cl)cn2)cc1
Yield: 41 %

Procedure:
5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and 4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (2.2 g, 40%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 2H), 7.74 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]#[N:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[NH4+].[Cl-]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)nc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3ccc(-c4nnn[nH]4)cc3nc2-c2ccc(F)cc2)cc1

Procedure:
A solution of 2,3-bis(4-fluorophenyl)quinoxaline-6-carbonitrile (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), NaN3 (500 mg, 7.69 mmol, 17.59 equiv), and NH4Cl (116 mg, 2.19 mmol, 5.00 equiv) was stirred for 4 h at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 7×50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated in vacuo, washed with dichloromethane, resulting in 34 mg (20%) of 2,3-bis(4-fluorophenyl)-6-(1H-tetrazol-5-yl)quinoxaline as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.CCN(CC)CC.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:1][N:2]1[C:6]([N:7]2[CH2:8][CH:9]=[C:10]([O:13][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][CH2:12]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1
Reactant: C[Si](C)(C)Cl
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc([N+](=O)[O-])c1N1CC=C(O[Si](C)(C)C)CC1
Temperature: 90 °C
Yield: 59 %

Procedure:
Three identical solutions of piperidin-4-one hydrochloride hydrate (1.84 g, 12.0 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.3 g, 8.0 mmol) and potassium fluoride (1.86 g, 32 mmol) in dry DMSO (20 mL) were heated in a microwave at 100° C. for 12 hr. The mixtures were combined, poured into water (700 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.97 g, 36%). To a solution of this ketone in DMF (40 mL) was added NEt3 (3.05 mL, 21.9 mmol) and chlorotrimethylsilane (1.55 mL, 12.3 mmol). The reaction vessel was sealed and the mixture heated at 90° C. for 16 hr. The mixture was cooled and the product extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine as a yellow gum (1.53 g, 59%). This gum was dissolved in MeCN (130 mL) and cooled to 0° C. A solution of SelectFluor® (1.99 g, 5.61 mmol) in 2:1 MeCN:DMF (10 mL) was added dropwise over 20 min and the mixture stirred at between −5° C. and 0° C. for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (40 mL). The product was extracted into EtOAc (50 mL) and DCM (50 mL), and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a pale yellow solid (1.23 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.04 (ddd, J=48.3, 8.2, 5.7 Hz, 1H), 3.89 (s, 3H), 3.77-3.64 (m, 2H), 3.64-3.51 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.72 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][C@H:12]([CH3:16])[CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([N:10]3[CH2:15][CH2:14][O:13][C@H:12]([CH3:16])[CH2:11]3)=[O:9])[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: C[C@@H]1CN(C(=O)c2cccc(Br)n2)CCO1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: C[C@@H]1CN(C(=O)c2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)CCO1

Procedure:
The title compound was prepared as described Example 1 using (2R)-4-[(6-bromopyridin-2-yl)carbonyl]-2-methylmorpholine (133 mg, 0.47 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (137 mg, 0.47 mmol) as starting materials
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].N1C(C)=CC=CC=1C.[CH3:14][NH:15][C@H:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:14][N:15]([C@@H:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:23])[P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN[C@H](C)c1ccccc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@H](c1ccccc1)N(C)P(=O)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
To a cooled (ice/water bath) solution of phosphorus oxychloride (2.83 mL, 30.3 mmol) in DCM (30 mL) was added sequentially, dropwise, and with stirring 2,6-lutidine (7.06 mL, 60.6 mmol) and a DCM solution of (R)-(+)-N,a-dimethylbenzylamine (3.73 g, 27.6 mmol). After 5 minutes, the bath was removed and reaction mixture allowed to warm to ambient temperature. After 1 hour, the reaction solution was washed with a citric acid solution (50 mL×3, 10% w/v aq), dried (MgSO4), filtered through SiO2 and concentrated to provide the title compound (3.80 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C19H25N4O4P 404.2. found m/z=403.1 (M−1).
Reaction SMILES: [F:1][CH:2]1[CH:7]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=[O:21])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]([C:32]2[CH:42]=[C:41]([CH3:43])[C:35]3[N:36]([CH3:40])[C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)=[O:31])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][N:36]1[C:35]2[C:41]([CH3:43])=[CH:42][C:32]([C:30]([C:25]3[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([N:4]4[CH2:5][CH2:6][CH:7]([N:8]5[CH2:14][CH2:13][C:12]6[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=6[NH:10][C:9]5=[O:21])[CH:2]([F:1])[CH2:3]4)[CH:24]=3)=[O:31])=[CH:33][C:34]=2[O:38][C:37]1=[O:39]
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1F)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)nc(C)n3)CC1F)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
82 mg (0.28 mmol) 3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 85 mg (0.27 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.10 mL (0.56 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[C:13]([F:27])[CH:12]=2)=[O:9])[C:4](=[O:28])[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:52].O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:52][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:28])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][C:13]=2[F:27])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)picolinamide (0.4 g, 0.86 mmol) and PhI(OAc)2 (419 mg, 1.5 mmol) in a mixture of EtOAc (8 mL), MeCN (8 mL) and H2O (4 mL) was cooled to 0° C. and stirred for 30 minutes. The reaction was then allowed to warm to rt, and stirred for another 8 h. The mixture was diluted with NaHCO3 (aq., 60 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a white solid (0.21 g, 56%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([O:4][C:5]([NH:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)[C:9]([O:11]C)=[O:10])=[O:6])[CH3:3].O.[OH-].[Li+]>CO.O>[CH3:3][C:2]([CH3:32])([O:4][C:5]([NH:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:18][CH2:17]1)[C:9]([OH:11])=[O:10])=[O:6])[CH3:1]
Reactant: COC(=O)[C@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
A mixture of 3.55 g (8.0 mmol) of methyl (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoate and 0.40 g (9.6 mmol) of lithium hydroxide monohydrate in 15 ml of methanol and 5 ml of water is stirred for 18 h at room temperature. The methanol is evaporated off under reduced pressure and the mixture is then cooled to 0° C. and acidified to pH 2 with aqueous 1N hydrochloric acid solution, and then extracted twice with 150 ml of ethyl acetate. The resulting extract is washed with 100 ml of saturated sodium chloride solution and then dried over sodium sulphate and filtered, and the residue obtained is concentrated. 3 g of (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoic acid are obtained in the form of a white powder, which is used without further purification in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[OH:12])=[O:5])[CH3:2].N12CCCN=C1CCCCC2.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[S:27]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[O:12][C:26](=[S:27])[N:25]([CH3:29])[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C)nc1O
Reactant: CN(C)C(=S)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(C)nc1OC(=S)N(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a mixture of 4-hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (7.2 g, 37.4 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (11.2 ml, 74.8 mmol) in DMF (50 ml) is added N,N-dimethyl-carbamothioyl chloride (6.94 g, 56.1 mmol). The mixture is stirred at RT for 14 h and at 60° C. for 3 h, poured onto water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic layers are washed with water (2×50 ml), dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel, 10% EtOAc/hexane) to give 4-(dimethyl-carbamothioyl)oxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (5.7 g, 20.7 mmol, 55%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:30])OC(C)(C)C)=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:7]=1)[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:41]=C=O)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:41][C:24]([NH:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:16][CH:17]=2)=[O:30])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: CCc1nc(-c2cccc(C)n2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: CCc1nc(-c2cccc(C)n2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 26 from tert-butyl 2-{4-[2-ethyl-4-(6-methylpyridin-2-yl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonyl isocyanate. MS (ESI) m/z 524 [M+H]+, 522 [M−H]−, 1H-NMR (DMSO d-6)δ1.20 (3H, t, J=7.3 Hz), 2.49 (3H, s), 2.67 (2H, q, J=7.5 Hz), 2.78 (2H, t, J=7.1 Hz), 3.25-3.32 (2H, m), 6.66 (1H, t, J=5.5 Hz), 7.10 (2H, 1, J=6.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.4 Hz), 7.7-7.76 (4H, m), 7.93 (1H, d, J=8.6 Hz).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:4]=1.Br.CCOC(C)=O>C(O)(=O)C>[CH3:28][C:11]1[N:10]=[C:9]([C:8]2[C:3](=[O:2])[NH:4][C:5]([NH:29][CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[N:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[CH:17]=1
Reactant: COc1nc(NCC(C)(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cnc(NCC(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
A solution of 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-N-neopentylpyrimidin-2-amine (0.081 g, 0.176 mmol) in acetic acid (2 mL) was treated with HBr (48% aq, 0.080 mL, 0.705 mmol), heated at 80° C. for 6 h, then cooled to RT overnight. The mixture was treated with ice and EtOAc, neutralized with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness. The material was suspended in MeCN, heated to near-reflux and allowed to stand at RT for 3 h. The resulting solid was collected via filtration to afford 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(neopentylamino)pyrimidin-4(3H)-one (44 mg, 56%). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 8.68 (s, 1H), 8.35 (d, J=6.6 Hz, 1H), 8.28-8.23 (m, 2H), 7.96 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.22 (d, J=3.0 Hz, 1H), 6.73 (br s, 1H), 6.60 (dd, J=5.1, 2.3 Hz, 1H), 3.86 (s, 3H), 3.22 (d, J=6.2 Hz, 2H), 2.34 (s, 3H), 0.91 (s, 9H); MS (ESI) m/z: 446.2 (M+H+).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:19])[C:11]=1Cl)(=O)[CH3:8].C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:8][C:7]1[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:19])[C:11]=2[S:1][C:2]=1[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CS
Reactant: CC(=O)c1c(Cl)n(C)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1sc2c(c1C)c1ccccc1n2C
Reaction time: 8 h

Procedure:
450 μl of methyl 2-mercaptoacetate was added to a slurry of 870 mg of (76) and 1.2 g of K2CO3 in 10 ml of MeOH. The reaction was stirred overnight. 30 ml of water was added, stirring continued for 1 hour, and the product filtered off giving 160 mg of product. Recrystallization from MeOH gave 30 mg of (77). M.p. 165.5°-166.8° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CCSCC2)c2ncnc(NCc3ccccc3)c2n1
Reactant: C1CNCCN1
Product: c1ccc(CNc2ncnc3c(N4CCSCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 118 from 8-benzylamino-2-chloro-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 94°-96° C.) and piperazine.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[N:9][CH:10]=1>[N+]([O-])([O-])=O.[Ag+]>[F:21][C:4]([F:20])([F:3])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([OH:1])=[O:17])=[CH:14][CH:13]=2)=[N:9][CH:10]=1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To aq. NaOH (3.2 g, 80 mmol) was added silver nitrate (3.4 g, 40 mmol) and stirred for 10 min., then the mixture was cooled to 0° C. and the above aldehyde (4.62 g, 17 mmol) was added. The mixture was stirred overnight, then filtrate through celite. The filtrate was collected and acidified with conc. HCl. The solid was collected by filtration and dried under vacuum to give 4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid. (3.5 g)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1CCCCC1>C(O)C>[CH:17](=[N:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccnc2)n[nH]c1N=Cc1ccccc1
Yield: 57 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in 10 mL of ethanol and benzaldehyde (463 μL, 1.0 eq.) and piperidine (0.10 eq, 47 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-(benzylideneamino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess benzaldehyde. Product was allowed to dry under vacuum for 1 hr (800 mg, 57% yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([NH2:49])([CH3:48])[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)CCC>[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([NH:49][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)([CH3:48])[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(N)CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC1(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Yield: 42.8 %

Procedure:
To a solution of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (580 mg, 1.7 mmol) in n-butanol (20 mL) were added diisopropylethylamine (DIPEA) (1.4 mL, 8.4 mmol) and 3-Amino-3-methyl-piperidine-1-carboxylic acid benzyl ester (420 mg, 1.7 mmol). The mixture was heated to reflux overnight, and LCMS showed 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine consumed. The reaction mixture was purified by column chromatography (eluting with 30˜35% ethyl acetate in hexane) to give 400 mg (43%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-methyl-piperidine-1-carboxylic acid benzyl ester. LCMS (Method J, ESI): RT=1.32 min, m+H=549.8; 1H NMR (400 MHz, CDCl3) δ: 9.60 (s, 1H), 9.10 (s, 1H), 8.20 (m, 2H), 7.70-7.50 (m, 4H), 7.40-7.30 (m, 5H), 5.34 (m, 2H), 3.90-3.80 (m, 1H), 2.30-2.20 (m, 1H), 1.90-1.50 (m, 9H).