Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][S:13]2(=[O:19])=[O:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.CO.N([O-])=[O:24].[Na+]>O>[O:18]=[S:13]1(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][N:12]1[C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:24])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)cc(N2CCCCS2(=O)=O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(O)cc(N2CCCCS2(=O)=O)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 3.8 %

Procedure:
To a solution of methyl 3-amino-5-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)benzoate (D267) (7.5 g, 26.4 mol, 1 equiv) in a 2N aqueous HCl solution (75 ml) and MeOH (75 ml) at 0° C. was added NaNO2 (4.0 g, 58.1 mmol, 2.2 equiv) portionwise over 20 min. MeOH (50 ml) and H2O (200 ml) were added and the resulting mixture was stirred at 95° C. for 1 h then cooled to room temperature. Most of the MeOH was removed in vacuo and the resulting aqueous phase was extracted with AcOEt. The insoluble material was filtered off to give methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-5-hydroxybenzoate (D) (0.63 g, 8%). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown residue which was redissolved in AcOEt. The organic phase was extracted with a saturated aqueous Na2CO3 solution and the aqueous phase was extracted three times with Et2O then acidified to pH 1 and re-extracted three times with AcOEt. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-5-hydroxybenzoate (D268) (2.2 g, 30%).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=1>C1COCC1.CN(C=O)C.O>[Br:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])=[CH:37][CH:38]=1
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)cc3)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
Dissolved 310 mg (3.68 mmol) 2-butynoic acid in 20 ml THF and chilled to 0° C. under N2. Added 480 μl (3.68 mmol) isobutyl chloroformate and 410 μl (3.72 mmol) N-methylmorpholine. Stirred for 20 minutes and dropwise added a solution of 500 mg (1.47 mmol) 6-amino-4-[(4-bromophenyl)amino]-3-quinolinecarbonitrile in 1 ml DMF and 10 ml THF. Removed ice bath after 15 minutes and stirred at 25° C. overnight. Stripped solvent, slurried residue with water and collected solids. Boiled solids in ethyl acetate, collected, and dried in vacuo, giving 341 mg of yellow solid: mass spectrum (electrospray m/e): M+H=405.1, 407.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSc1nnc(N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a mixture of 3.9 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 4.2 g of potassium carbonate and 50 ml of ethanol was gradually added 5 g of ethyl bromoacetate under ice cooling. Then, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 200 ml of water followed by extraction with ethyl acetate. After washing with water, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The solid obtained was washed with toluene and dried to obtain 2.7 g of ethyl [(5-amino-1,3,4-thiadiazol-2-yl)thio]-acetate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:39]([NH:41][C@H:42]([C:48]([NH:50][C@H:51]([C:57]([NH:59][C@H:60]([C:63]([NH:65][C@H:66]([C:72]([NH:74][C@H:75]([C:79]([N:81]1[CH2:118][CH2:117][CH2:116][C@H:82]1[C:83]([NH:85][C@H:86]([C:91]([NH:93][C@H:94]([C:98]([NH:100][C@H:101]([C:105]([NH:107][C@H:108]([C:113]([OH:115])=[O:114])[CH2:109][CH:110]([CH3:112])[CH3:111])=[O:106])[C@@H:102]([CH3:104])[OH:103])=[O:99])[CH:95]([CH3:97])[CH3:96])=[O:92])[CH2:87][CH:88]([CH3:90])[CH3:89])=[O:84])=[O:80])[C@@H:76]([CH3:78])[OH:77])=[O:73])[CH2:67][CH2:68][C:69](=[O:71])[NH2:70])=[O:64])[CH2:61][OH:62])=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[OH:46])=[O:40])[CH2:37][OH:38])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].[OH:119]O>C(O)(=O)C.[Pt]>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:39]([NH:41][C@H:42]([C:48]([NH:50][C@H:51]([C:57]([NH:59][C@H:60]([C:63]([NH:65][C@H:66]([C:72]([NH:74][C@H:75]([C:79]([N:81]1[CH2:118][CH2:117][CH2:116][C@H:82]1[C:83]([NH:85][C@H:86]([C:91]([NH:93][C@H:94]([C:98]([NH:100][C@H:101]([C:105]([NH:107][C@H:108]([C:113]([OH:115])=[O:114])[CH2:109][CH:110]([CH3:112])[CH3:111])=[O:106])[C@@H:102]([CH3:104])[OH:103])=[O:99])[CH:95]([CH3:96])[CH3:97])=[O:92])[CH2:87][CH:88]([CH3:90])[CH3:89])=[O:84])=[O:80])[C@@H:76]([CH3:78])[OH:77])=[O:73])[CH2:67][CH2:68][C:69](=[O:71])[NH2:70])=[O:64])[CH2:61][OH:62])=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])=[O:49])[CH2:43][CH2:44][C:45](=[O:46])[OH:47])=[O:40])[CH2:37][OH:38])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:27])[CH2:22][CH2:23][S:24]([CH3:25])=[O:119])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN)C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)[C@@H](C)O)C(C)C)[C@@H](C)O)[C@@H](C)O
Reactant: OO
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CCS(C)=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 mg of the peptide obtained in Example I is dissolved in 20 ml glacial acetic acid, after which 0.08 ml 30% hydrogen peroxide is added. The mixture is stirred for about 1 hour at room temperature, after which 300 mg platinum Black in glacial acetic acid is added to the mixture and the whole is stirred for about a further 15 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[C:13](C1CC(=O)NC1=O)([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14].Cl>CC(C)=O.C([O-])(O)=O.[Na+]>[CH:28]1[C:29]2[CH:17]([CH2:16][O:15][C:13]([NH:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=3[O:11][CH3:12])[C:5]([OH:7])=[O:6])=[O:14])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: O=C1CC(C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
A suspension of 3-amino-4-methoxybenzoic acid (1.00 g, 6.0 mmol) in acetone (15 mL) was treated portionwise and alternately with Fmoc-succinimide (2.63 g, 7.8 mmol) in acetone (15 mL) and saturated aqueous NaHCO3 to keep the pH of the solution between 8-9, stirred at room temperature for 18 hours, treated with 3M HCl, and filtered. The solid was washed sequentially with water and dichloromethane and dried under vacuum to provide 1.54 g (66%) of the desired product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH:11]([P:13]([CH3:18])(=[O:17])[O:14]CC)[OH:12])=O)(C)(C)C.C1OC1C>Cl.CO>[NH2:8][CH2:9][CH:10]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[CH:11]([P:13]([CH3:18])(=[O:14])[OH:17])[OH:12]
Reactant: CCOP(C)(=O)C(O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: CC1CO1
Agent: Cl
Solvent: CO
Product: CP(=O)(O)C(O)C(CN)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 0.64 g of ethyl 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl(methyl)phosphinate in 12 ml of concentrated aqueous hydrochloric acid is heated to reflux for 5 hours. The mixture is then cooled and evaporated to dryness in vacuo. The residue is repeatedly co-evaporated with methanol until the hydrochloride salt is obtained as a foam. This is dissolved in 50 ml of methanol and treated with 25 ml of propylene oxide after 40 minutes stirring at room temperature a solid precipitates, and the suspension stirred for a further 11/2 hours. The solid is collected by filtration washed with propylene oxide and ether and dried the solid is redissolved in methanol at elevated temperature and filtered. Concentration in vacuo and dilution with ether affords a solid which is collected and dried to give 3-amino-2-(4-chlorophenyl)-1-hydroxy-propyl(methyl)phosphinic acid, m.p. 240°-241° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH3:17][N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([CH:11]1[CH2:10][CH2:9][C:8](=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CNc1ccccc1
Reactant: O=C1CCC(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)C1CCC(=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Oxalyl chloride (0.89 g, 7.0 mmol) and a few drops of dry DMF are added to a stirred solution of 4-oxo-cyclohexanecarboxylic acid (0.50 g, 3.5 mmol) in CH2Cl2 (7 ml) and the reaction is kept stirring at rt overnight. The volatiles are removed under reduced pressure, the residue is azeotroped with toluene and dried under high vacuum yielding crude acid chloride. This material is reacted without further purification with N-methylaniline (0.16 g, 1.5 mmol) in CH2Cl2 (7 ml) in the presence of DIEA (0.58 g, 4.5 mmol). After stirring overnight at rt, saturated aqueous NaHCO3 is added and the mixture extracted three times with CH2Cl2. The combined organic layers are dried over Na2SO4 and evaporated. The residue is column chromatographed on silica gel (hexane/EtOAc 2:1) and the title compound is obtained as a pale yellow solid (0.47 g) in 57% yield. tR (LC-4) 0.89 min; ESI-MS (positive ion): m/z 231.98 [M]+ (calcd 231.13 for C14H17NO2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:23]3[CH2:28][CH2:27][CH:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:23]3[CH2:28][CH2:27][CH:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Reactant: CC(C)c1noc(C2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(C2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Temperature: 160 °C
Yield: 18.8 %

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 66 mg, 0.35 mmol), 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 23; 60 mg, 0.17 mmol) and potassium carbonate (105 mg, 0.76 mmol) in DMF (1.5 mL) was heated in the microwave at 160° C. for 10 min. Saturated aqueous sodium carbonate solution was added to the cooled reaction mixture. The precipitate was filtered, and the filtrate was extracted with ethyl acetate. The extracts were dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 5% methanol/dichloromethane, to give 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (16 mg, 19%) as a white solid. Mass spectrum M+=500.9.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[OH:10].[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:13](=[O:14])[N:12]([CH3:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1nc2ccccc2s1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1nc2ccccc2s1)c1ccccc1

Procedure:
The title product was prepared from 2-benzothiazolol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (70%, white crystals). HPLC-MS: m/z=307.1 (M+1); Rt: 4.24 min, purity 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])=[CH:17][C:16]=3[F:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:22][CH2:25][CH2:24][N:23]=4)=[CH:17][C:16]=3[F:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NCCO)c1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(F)c1
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)N1CCC(=Cc2ccc(C3=NCCO3)cc2F)CC1

Procedure:
0.4 g (0.95 mmol) of 1-(4-chlorobenzoyl)-4-[2-fluoro-4-(2-hydroxyethylaminocarbonyl)benzylidene]piperidine in 20 ml of tetrahydrofuran are treated with 0.3 g (1.1 mmol) of methyl N-(triethylamoniosulphonyl)carbamate (Burgess reagent) in portions, at boiling temperature, during the course of 45 minutes. The mixture is heated for a further 2 hours and evaporated down, and the residue is mixed with water, the mixture is extracted three times with methylene chloride, the extract is dried with anhydrous sodium sulphate and evaporated down, and the residue is purified on a Silica gel column (ethyl acetate/petroleum ether=10:4, v/v). 0.105 g (26% of theory) of the title compound of melting point 158°-160° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22](O)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22]([N:36]2[CH2:35][CH2:34][N:33]([CH:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH2:38][CH2:37]2)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C3CCN(C)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (114 mg, 0.706 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (250 mg, 0.673 mmol) in dichloromethane (15 ml), and the mixture was stirred for 1 h at room temperature. A solution of 1-(1-methylpiperidin-4-yl)piperazine (123 mg, 0.673 mmol) in dichloromethane (5 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was then extracted with water (20 ml) and saturated sodium chloride solution (20 ml), and the organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using dichloromethane/methanol (97:3→90:10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:14][CH3:15].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([N:18]([O:19][CH3:20])[CH3:17])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)C(=O)N(C)OC)ccc1F
Reaction time: 5 h

Procedure:
To a solution of 2-(4-fluoro-3-methoxyphenyl)-2-methylpropanoic acid (114.75 g, 4.71 mmol) in DCM (2 L) was added N,O-dimethylhydroxylamine hydrochloride (79 g, 0.81 mol), EDCI (145 g, 0.72 mol), DMAP (33 g, 0.27 mol), and DIPEA (471 mL, 2.7 mol). The resulting mixture was stirred 5 h and quenched with H2O (1 L). The organic layer was washed with 1N HCl (1 L×2), satd NaHCO3 (1 L), and brine (1 L) successfully. The organic phase was dried over MgSO4 and concentrated at reduced pressure to afford 2-(4-fluoro-3-methoxyphenyl)-N-methoxy-N,2-dimethylpropanamide as yellow color oil (123 g, 89%). 1H NMR (400 MHz, CDCl3): δ 7.03 (t, 1H), 6.83 (d, 1H), 6.80 (m, 1H), 3.89 (s, 3H), 3.12 (s, 3H), 2.77 (s, 3H), 1.53 (s, 6H).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[O:15]=O>CN(C=O)C.Cl[Cu]>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[O:15])([O-:13])=[O:12]
Reactant: CN(C)C=Cc1ccccc1[N+](=O)[O-]
Reactant: O=O
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 88.8 %

Procedure:
The crude solution of β-dimethylamino-2-nitro-styrene, prepared analogously to Example 1, was diluted with 250 ml of DMF and 3 g of CuCl were added. The mixture was areated at 50° C. for 45 min. using oxygen and the solvent was then removed. After customary working-up, it was possible to isolate 88.8% of o-nitrobenzaldehyde, based on the o-nitro-toluene employed. The proportion of secondary components in the precipitated product was only 0.8%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)O1.Br[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([N:31]=[N:32][N:33]=2)[C:29]=1[CH3:30]>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[CH3:30][C:29]1[N:28]2[N:31]=[N:32][N:33]=[C:27]2[CH:26]=[CH:25][C:24]=1[C:9]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2
Reactant: Cc1c(Br)ccc2nnnn12
Reactant: CC1(C)OB(c2cc(C(F)(F)F)cc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1c(-c2cc(C(F)(F)F)cc3[nH]ncc23)ccc2nnnn12
Temperature: 130 °C

Procedure:
To a 20 mL microwave vial was added a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (50 mg, 0.160 mmol), 6-bromo-5-methyltetrazolo[1,5-a]pyridine (34.1 mg, 0.160 mmol), and PdCl2(dppf) (6.59 mg, 8.01 μmol) in dioxane (4 mL) and aqueous saturated NaHCO3 (2 mL). The resulting yellow suspension was heated at 130° C. for 30 minutes in a microwave reactor. The reaction mixture was subsequently purified by preparative HPLC, eluting with a gradient of 45-65% acetonitrile in H2O (containing 10 mM NH4HCO3). The product fractions were combined and dried to give the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 2.83 (s, 3H), 7.51 (d, J=1.01 Hz, 1H), 7.91 (d, J=9.09 Hz, 1H), 8.04 (s, 1H), 8.06 (s, 1H), 8.10 (dd, J=9.09, 0.76 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C14H9F3N6, 319.1. found 319.3.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.CN(C=O)C.[H-].[Na+].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34]>CCOC(C)=O.O>[C:33]([C:32]1[CH:35]=[CH:36][C:37]([N:3]2[CH:4]=[CH:5][C:6]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:7][C:2]2=[O:1])=[C:30]([F:29])[CH:31]=1)#[N:34]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(C#N)cc3F)c(=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a mixture of tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (730 mg, 2.480 mmol, Step A of Example 132) and DMF (12 mL) at room temperature was added sodium hydride (114 mg, 2.85 mmol). After stirring at room temperature for 1 hr, 3,4-difluorobenzonitrile (345 mg, 2.480 mmol, Aldrich) was added and the reaction mixture was heated at 100° C. for 1.5 hrs and cooled to room temperature. The resulting mixture was diluted with EtOAc and water and the aqueous layer was extracted further with EtOAc (3×). The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound (602.4 mg, 58.7%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.47-7.64 (m, 3 H), 7.10 (d, J=7.70 Hz, 1 H), 6.04 (dd, J=7.70, 2.20 Hz, 1 H), 5.96 (d, J=2.20 Hz, 1 H), 4.41-4.55 (m, 1 H), 3.65-3.80 (m, 2 H), 3.27-3.39 (m, 2 H), 1.91-2.04 (m, 2 H), 1.71-1.84 (m, 2H), 1.48 (s, 9 H). MS (ESI) 358 (M+H-C4 H8).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH2:25]CCN4CCOCC4)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:34])([CH3:3])[CH3:2].[O-]O.C1(C(C)C)C=CC=CC=1>C(OCCCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:34])([CH3:3])[CH3:2]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)CCCN4CCOCC4)cc3)n2)n1C(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CCCCOC(C)=O
Solvent: CC(C)c1ccccc1
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(C)(=O)=O)cc3)n2)n1C(C)C
Temperature: 50 °C
Yield: 43.3 %

Procedure:
Titanium isopropoxide (188 μl, 0.62 mmol) was added to a mixture of 4-(1-isopropyl-2-methylimidazol-5-yl)-2-[4-(methylthio)anilino]pyrimidine (Method 86; 700 mg, 2.06 mmol) in butyl acetate (4.9 ml) and the mixture was heated to 50° C. Cumene hydroperoxide (800 μl, 4.32 mmol) was added over 40 minutes and the mixture was allowed to cool to 20° C. The resulting precipitate was collected by filtration, washed with butyl acetate and dried at 50° C. under vacuum to give the title compound (331 mg, 42%).