Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5](O)([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])C)C.[CH3:14]I.Cl>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH3:14][CH2:12][CH:10]=[CH:9][CH2:8][CH2:7][CH2:5][CH2:4][CH3:3]
Reactant: CCC(C)(O)CCC=C(C)C
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC=CCCCCC
Temperature: 37.5 °C
Reaction time: 8 h

Procedure:
To a dry 2 L multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an additional funnel, 400 ml of THF, 44 g of NaH, and 21.2 g of dihydroethyl linalool were added and heated to 35-40° C. 170 g of dihydrolinalool g was then added to the reaction mixture dropwise over 2 hours. The mixture was aged for 8 hours. 9 g of HMPA (available from Aldrich Chemical Company) was added and the mixture was stirred. 144 g of CH3I was added dropwise to the reaction mixture, further aged for two hours and then sampled hourly until maximum conversion was reached. The mixture was cooled and 800 ml of 5% HCl solution was added, allowed to settle, and the organic layer was separated. The aqueous layer was extracted with 3×100 ml of toluene and then dried over MgSO4 to provide 3-nonene, 7-methoxy-3,7-dimethyl-.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.[C:14](=[O:16])=[O:15].O>O1CCCC1>[F:8][C:4]1[N:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15]
Reactant: O=C=O
Reactant: Fc1cccc(F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To 2,6-difluoropyridine (58, 7.10 g, 0.0617 mol) in tetrahydrofuran (150.0 mL) under an atmosphere of nitrogen at −78° C., n-butyllithium (26.0 mL, 2.50 M in hexane) was added slowly. After 30 minutes, dry ice (3.0 g) was added to the reaction. After 1 hour, the reaction was allowed to warm to room temperature, then poured into water and extracted with ethyl acetate. The aqueous layer was acidified with 1 N HCl to pH=4-5 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound as a light yellow solid (59, 5.6 g, 57.0%).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1>>[CH3:10][C:11]1[C:16]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: N#Cc1cccnc1F
Reactant: Cc1ncccc1O
Product: Cc1ncccc1Oc1ncccc1C#N

Procedure:
2-Fluoro-nicotinonitrile was reacted with 2-methyl-pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 212 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:15]=2[CH3:16])=[N:7][CH:8]=1.[OH:22][C:23]1[C:27]([CH:28]=[O:29])=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.CN(C)C=O.[H-].[Na+]>O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:13]1[O:14][C:15]([CH3:16])=[C:11]([CH2:10][O:9][C:6]2[N:7]=[CH:8][C:3]([CH2:2][O:22][C:23]3[C:27]([CH:28]=[O:29])=[CH:26][N:25]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:24]=3)=[CH:4][CH:5]=2)[N:12]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a mixture of 5-chloromethyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridine (0.58 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.07 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give 3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.56 g, yield 77%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22](O)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1.[CH3:25][O:26][CH2:27]Cl>C(N(CC)CC)C>[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1
Reactant: Oc1ccc2nc(-c3ccc(I)cc3)sc2c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1ccc2nc(-c3ccc(I)cc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 30 mg, 0.76 mmol) was added to a DMF (2 mL) solution of 5 (225 mg, 0.64 mmol), cooled in an ice bath. After stirring at 0° C. for 1 h, chloromethyl methyl ether (100 μL, 1.33 mmol) and triethylamine (0.2 mL) were added. The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with pH 7 buffer solution (10 mL). The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash chromatography on silica gel (CH2Cl2), to give 2-(4-iodophenyl)-6-(methoxymethyl)-1,3-benzothiazole (6) (237 mg, 93.7%) as a white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH3:26][C:27]1[C:28]([C:34]([CH:36]2[CH2:38][CH2:37]2)=O)=[N:29][CH:30]=[CH:31][C:32]=1[Cl:33]>C1COCC1>[CH:36]1([C:34]([C:28]2[C:27]([CH3:26])=[C:32]([Cl:33])[CH:31]=[CH:30][N:29]=2)=[CH:2][O:3][CH3:4])[CH2:38][CH2:37]1
Reactant: Cc1c(Cl)ccnc1C(=O)C1CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C(c1nccc(Cl)c1C)C1CC1
Temperature: 40 °C
Yield: 82.1 %

Procedure:
A solution of methoxymethyl triphenylphosphonium chloride (17.9 g, 52.3 mmol) in dry THF (80 mL) was treated with NaH (2.79 g, 69.8 mmol) at 0° C. for 3 h. To this mixture was added a solution of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanone (6.82 g, 34.9 mmol) in dry THF (20 mL). The reaction mixture was heated at 40° C. overnight. The reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated to dryness. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 3:1) to afford the title compound (6.41 g, 82%). ESI-MS m/z: 224 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ ppm: 8.31 (d, J=5.4 Hz, 0.5; H), 8.23 (d, J=5.4 Hz, 0.5; H), 7.17 (d, J=5.4 Hz, 1H), 6.13-6.16 (m, 1H), 3.70 (s, 1.5; H), 3.56 (s, 1.5; H), 2.38 (s, 1.5; H), 2.31 (s, 1.5; H), 1.91-1.94 (m, 0.5; H), 1.63-1.65 (m, 0.5; H), 0.66-0.72 (m, 1H), 0.56-0.62 (m, 1H), 0.35-0.38 (m, 1H), 0.26-0.33 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([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:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][C:26]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2)=[O:27]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([C:26](=[O:27])[NH:25][CH2:24][CH2:23][OH:22])=[CH:36][CH:35]=4)[CH:31]=[CH:32]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: O=C(NCCO)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C(=O)NCCO)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N-(2-hydroxyethyl)-1H-indole-5-carboxamide (intermediate-19) (0.110 g, 48.0%).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[O:6][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:11]
Reactant: CN(C(=O)c1ccccc1O)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1C(=O)N(C)c1ccccc1
Yield: 97.9 %

Procedure:
A solution of N-methyl-N-phenylsalicylamide (13.5 g.), ethyl bromoacetate (10 g.) and anhydrous potassium carbonate (8.4 g.) in N,N-dimethylformamide (90 ml.) was stirred at room temperature for 7 hours. The resultant mixture was added to water and extracted with diethyl ether, and the extract was washed with 10% aqueous solution of sodium hydroxide and water in turn, dried over magnesium sulfate and then evaporated under reduced pressure to give oily ethyl 2-[2-(N-methyl-N-phenylcarbamoyl)phenoxy]acetate (18.23 g.).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(Cl)Cl>[C:1]([C:5]1[C:9]([Cl:18])=[C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)Nc1cc(C(C)(C)C)no1
Solvent: ClCCl
Product: COC(=O)Nc1onc(C(C)(C)C)c1Cl
Yield: 102.5 %

Procedure:
To a solution of methyl 3-t-butyl-5-isoxazolylcarbamate (2.56 g) in methylene chloride (13 ml), sulfuryl chloride (1.81 g) is added dropwise, and the resultant mixture is refluxed for 2 hours. The reaction mixture is evaporated to remove the solvent, whereby methyl 3-t-butyl-4-chloro-5-isoxazolylcarbamate (3.08 g) is obtained as an oil. IR: 1748, 1642 cm-1 (CC14).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[S:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](SCC=Cc2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](SCCCc2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A solution of 2 (800 mg) in ethyl acetate (10 ml) and acetic acid (10 μl) containing 10% palladium-on-charcoal (400 mg) is hydrogenated overnight at room temperature. The catalyst is filtered off and washed with ethyl acetate. The combined filtrates are evaporated in vacuo to give 6 (780 mg, 97%); m.p. 73°-74° C. (ethyl ether-petroleum ether); [α]D27 +86.0±0.9° (C 1.08, chloroform).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O)(C(F)(F)F)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][CH2:32][CH2:31][CH2:30][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCCCN1CCCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCN3CCCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(pyrrolidin-1-yl)propan-1-amine as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80-1.96 (m, 4H) 1.97-2.08 (m, 2H) 2.44 (s, 3H) 2.91-3.09 (m, 2H) 3.21 (dt, J=10.36, 5.43 Hz, 2H) 3.38 (q, J=6.40 Hz, 2H) 3.49-3.64 (m, 2H) 7.67 (d, J=7.58 Hz, 1H) 7.74 (s, 2H) 8.03-8.33 (m, 1H) 8.43 (br. s., 2H) 8.85 (br. s., 1H) 8.88-8.98 (m, 1H) 9.50 (br. s., 1H) 12.61-13.62 (m, 1H). MS m/z [M+H]+ 431.2
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:65][N:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][N:66]5[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 7) (15 mg, 0.033 mmol, 1 eq), DIPEA (12 μl, 0.066 mmol, 2 eq) and TBTU (12 mg, 0.036 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 1-amino-4-methylpiperazine (5 mg) and DIPEA (13 μL). The RM was then stirred at rt for 3 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1([CH2:20][OH:21])[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH2:13][NH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]1[O:24][CH2:23]1>O.C(O)(=O)C>[OH:24][CH2:23][CH2:22][N:12]1[CH2:13][CH:14]([OH:19])[CH:15]([OH:18])[CH:16]([OH:17])[C:11]1([CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][OH:21]
Reactant: C1CO1
Reactant: O=C(NCC1(CO)NCC(O)C(O)C1O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCC1(CO)C(O)C(O)C(O)CN1CCO)c1ccccc1
Reaction time: 24 h

Procedure:
4.44 g of 2-benzoylaminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine (Preparation example 3) are dissolved in 65 ml of water and, after adding one drop of acetic acid, 6 ml of ethylene oxide are added at about 5° C. After stirring the mixture for 24 hours, the reaction has ended. The mixture is concentrated, the residue is dissolved in about 40 ml of methanol/water 2:1 and the solution is discharged onto a column 20 cm long and 3 cm wide which contains Amberlite® IR 120, H+ form. The column is washed thoroughly with methanol/water 2:1 and then eluted with 0.1% strength ammonia. The individual fractions are investigated by thin layer chromatography to determine their content and the fractions containing the desired product are concentrated. 2.4 g of N-hydroxyethyl-2-benzoylaminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine are obtained in the form of a solid foam.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:7][C:8]1([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:43])C=1>ClCCl>[CH3:4][C:2]([S:5]([NH:7][C:8]1([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[CH2:9][O:10][CH2:11]1)(=[O:43])=[O:6])([CH3:1])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)COC3)s2)c1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)(=O)C(C)(C)C)COC3)s2)c1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfinamide (Example 59, Step 2, 75 mg, 0.147 mmol) in dichloromethane (1.5 mL) was cooled to 0° C. m-CPBA (37.8 mg, 0.219 mmol) was added and the resulting mixture was warmed to room temperature. The reaction mixture was diluted with dichloromethane, washed with 2M NaOH (2×), saturated NaHCO3 (1×), brine (1×), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfonamide (45.6 mg, 0.086 mmol, 59.0% yield) as a light yellow solid. MS ESI: [M+H]+ m/z 510.1. 1H NMR (500 MHz, dmso) δ 10.29 (s, 1H), 8.83 (d, J=4.9, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.28 (d, J=4.9, 1H), 7.18 (s, 1H), 4.90 (dd, J=6.6, 33.0, 4H), 2.33 (s, 3H), 1.35 (s, 9H). rhSYK activity=+++
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl.[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[F:24][C:25]1([F:31])[CH2:30][CH2:29][N:28]([C:2]2[N:6]=[C:5]([N:7]3[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[CH2:9][CH2:8]3)[S:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: FC1(F)CCNCC1
Reactant: COc1ccc(CCN2CCN(c3nc(Br)ns3)CC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(CCN2CCN(c3nc(N4CCC(F)(F)CC4)ns3)CC2)cc1
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole (55 mg, 143 μmol), 4,4-difluoropiperidine hydrochloride (67.8 mg, 430 μmol) and DIPEA (185 mg, 251 μl, 1.43 mmol) in N-Methyl-2-pyrrolidinone (1 mL) was heated with microwave at 200° C. for 2.5 h. The amber reaction solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 41.8 mg (69%) of the title compound as off-white solid. MS (m/e): 424.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3ccc(F)cc3F)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3ccc(F)cc3F)c2O1

Procedure:
The title compound was prepared (0.062 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.132 g, 0.29 mmol) and methylamine (0.092 g, 2.9 mmol). mp 179-181° C.
Reaction SMILES: [CH2:1]([CH:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:26][CH2:27][CH2:28]Br.C([N-]C(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1>[CH2:1]([C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)([CH2:28][CH2:27][Br:26])[C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC(C#N)c1ccc(OC)c(OC)c1
Reactant: BrCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC(C#N)(CCBr)c1ccc(OC)c(OC)c1

Procedure:
45.2 g (0.1 mole) of α-(n-dodecyl)-α-(2-bromoethyl)-3,4-dimethoxyphenyl-acetonitrile (obtained by condensation of α-dodecyl-3,4-dimethoxy-phenylacetonitrile with 1,2-dibromoethane in toluene solution in the presence of lithium diisopropylamide) and 41.8 g of β-(N-ethyl)-3,4-dimethoxyphenethylamine were heated at 150° C. in an oilbath for two hours. 250 ml of toluene were added while the mixture was still hot and the precipitate of β-(N-ethyl)-3,4-dimethoxy-phenethylamine hydrobromide which separated out was filtered off with suction.
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])C.[Cl:21][C:22]1[C:28](Cl)=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(OC(=O)C)C>CS(C)=O>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CCOc1c(Nc2ccc([N+](=O)[O-])cc2O)c(=O)c1=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1c(Nc2ccc([N+](=O)[O-])cc2O)c(Nc2ccccc2Cl)c1=O
Temperature: 25 °C
Yield: 13.1 %

Procedure:
A solution of 3-ethoxy-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione (0.40 g, 1.44 mmol) and 2,3-dichloroaniline (0.34 g, 2.10 mmol) in 2 mL DMSO was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added, a precipitate formed. The filter cake was collected. Titration from acetone and hexanes gave 68 mg (11%) of 3-(2-chloroanilino)-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione. LCMS(H+) 394.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1.O.[NH2:27][NH2:28]>CCO>[NH:27]([C:14]([C:13]1[CH:18]=[CH:19][C:10]([NH:9][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:2][CH:3]=2)=[O:8])=[CH:11][CH:12]=1)=[O:15])[NH2:28]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 66 %

Procedure:
To a suspension of methyl 4-[([1,1′-biphenyl]-4-ylcarbonyl)amino]benzoate (880 mg, 2.66 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 7 days at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (3×2 mL) and water (3×2 mL), and drying under vacuo at rt for 6 hrs gave 585 mg of the title compound (66%) as a white solid in 96.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:4][CH:3]=1.[CH3:13][NH:14][NH2:15]>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:14]([CH3:13])[N:15]=[C:10]([NH2:11])[CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: N#CCC(=O)c1cccc(Br)n1
Solvent: CCO
Product: Cn1nc(N)cc1-c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 3-(6-bromo-2-pyridyl)-3-oxo-propanenitrile (1.71 g, 7.6 mmol, Preparation A.1) in ethanol (50 mL) was added methyl hydrazine (1.20 mL, 22.8 mmol). The resulting mixture was stirred for about 30 min at rt and then heated under reflux for about 4 h. After cooling to rt the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:2) to give 3-(6-bromo-2-pyridyl)-2-methyl-pyrazol-5-amine (1.56 g, 6.2 mmol, 81%) as an off white solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 3.57 (2 H, br s); 3.75 (3 H, s); 5.90 (1 H, s); 7.34 (1 H, d, J=8 Hz); 7.52 (1 H, t, J=8 Hz); 7.82 (1 H, d, J=8 Hz).