Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[C:11]([CH2:12][OH:13])=[CH:10][C:9]3[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2nc3c(C)cccc3cc2CO)c1
Temperature: 150 °C
Yield: 75.5 %

Procedure:
To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (300 mg, 1.45 mmol) in 1,4-dioxane/water (4 mL/1 mL) was added 3-methoxyphenylboronic acid (261 mg, 1.74 mmol), K2CO3 (400 mg, 2.9 mmol) and Pd(PPh3)4 (167 mg, 0.145 mmol). The mixture was degassed and heated in a microwave at 150° C. for 1 h. The solvent was removed in vacuo and the residue dissolved in DCM (50 mL) and washed with water (2×10 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo. Purification by column chromatography (SiO2, 10-20% EtOAc in Petrol 40-60) yielded the title compound (306 mg, 76%) as a colourless gum. δH (CDCl3) 8.25 (s, 1H), 7.66 (d, J 8.2 Hz, 1H), 7.54 (d, J 7.1 Hz, 1H), 7.32-7.45 (m, 2H), 7.21-7.26 (m, 2H), 6.96-7.00 (m, 1H), 4.79 (s, 2H), 3.85 (s, 3H), 2.81 (s, 3H), 2.06 (s, 1H). LCMS (ES+) 280 (M+H)+, RT 3.03 minutes (Method 5).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]=[CH2:17])[C:11]([CH2:18][C:19]#[C:20][CH3:21])=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH:2]=[CH2:3].[N:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:1]([O:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]=[CH2:17])[C:11]([CH2:18][C:19]#[C:20][CH3:21])=[CH:10][C:6]=1[C:7]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:34][CH:33]=1)=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OCC=C)c(C(=O)O)cc1CC#CC
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(OCC=C)c(C(=O)Nc2ccc(CN3CCOCC3)cc2)cc1CC#CC
Reaction time: 4 h
Yield: 86.8 %

Procedure:
2,4-bis-allyloxy-5 (but-2-ynyl)-benzoic acid (Example 1-4, IM07-c: 287 mg, 1 mmol) and 4-(morpholin-4-ylmethyl)-phenylamine (IM08-02: 193 mg, 1 mmol) were dissolved in dimethylformamide (4 mL) and mixed with 1-hydroxybenzotriazole monohydrate (176 mg, 1.3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg, 1.3 mmol) at 0° C., and the resulting mixture was stirred for 4 hours under ice cold conditions. The reaction mixture was mixed with water (40 mL) and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and then were concentrated. The residue was purified by silica gel column chromatography (hexane-ethylacetate=1:2-1:5) to obtain the title compound (F470-IM09: 0.40 g, yield 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:19][CH2:20][CH2:21][N:22]1[C:27]2[CH:28]=[CH:29][C:30]([S:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][C:26]=2[O:25][CH2:24][C:23]1=[O:46])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]([CH2:19][CH2:20][CH2:21][N:22]1[C:27]2[CH:28]=[CH:29][C:30]([S:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][C:26]=2[O:25][CH2:24][C:23]1=[O:46])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCN(C(=O)OCc1ccccc1)c1cccc[n+]1[O-])c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCN(C(=O)OCc1ccccc1)c1ccccn1)c1ccccc1
Temperature: 40 °C

Procedure:
To a solution of titanium (IV) chloride in tetrahydrofuran under nitrogen atmosphere, is added and equimolar amount of stannous chloride dihydrate, and the mixture is stirred 1 hour at room temperature. Then, a solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate is added and the mixture heated 3 hours at 40° C. After evaporation of the solvent, ice and aqueous sodium bicarbonate are added, the mixture extracted with ethyl acetate, and the organic layers are combined and dried over sodium sulfate. The solvent is evaporated and ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate is isolated by column chromatography. A solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate in acetic acid is treated with a solution of 30% hydrobromic acid in acetic acid at room temperature overnight. The solvent is evaporated under reduced pressure, and the residue is treated with a saturated sodium bicarbonate solution. The aqueous mixture is extracted with dichloromethane. The organic extracts are dried over sodium sulfate, evaporated to small volume and the product is purified by flash chromatography
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCCCCCNC1=C(c2ccccc2)S(=O)(=O)N(CCCC)C1=O
Yield: 49.9 %

Procedure:
A solution of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.110 g, 0.33 mmol) and hexylamine (0.100 g, 0.984 mmol) in DMF (0.5 mL) was heated in a microwave reactor at 140° C. for 25 mins. The residue was purified by preparative HPLC (Ace C8 column, 0.1M NH4OAc/MeCN, gradient) to give the title compound (0.060 g, 47%); 1H-NMR (400 MHz, CD3CN): δ 7.49-7.53 (m, 5H), 5.85 (bs, 1H), 3.66 8 (t, 2H), 2.85 (dd, 2H), 1.71-1.80 (m, 2H), 1.37-1.48 (m, 2H), 1.13-1.34 (m, 4H), 0.94-1.09 (m, 7H), 0.82 (t, 3H); Mass Spectrum: M+H 365.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][NH:27][C@@H:28]([CH:30]([CH3:32])[CH3:31])[CH3:29]>>[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][N:27]([C@@H:28]([CH:30]([CH3:31])[CH3:32])[CH3:29])[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:11]1[CH:20]=[CH:21][CH:22]=[C:9]([C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=2)[CH:10]=1
Reactant: CC(C)n1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: COC(CN[C@H](C)C(C)C)OC
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C(C)C)c2)c1)[C@H](C)C(C)C)OC

Procedure:
The subtitled compound (105 mg) was prepared from 3-(3-(1-isopropyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 20, Step iii)] and (R)—N-(2,2-dimethoxyethyl)-3-methylbutan-2-amine, prepared as in Preparation 4 using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=428 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.01 and 8.00 (2×s, 1H), 7.78 (s, 1H), 7.42-7.33 (m, 2H), 7.23 and 7.22 (2×t, J=7.8 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 4.59 and 4.43 (2×t, J=5.1 Hz, 1H), 4.53 (septet, J=7.0 Hz, 1H), 3.76-3.63 (m, 5H), 3.37-3.27 (m, 8H), 2.85 and 2.84 (2×t, J=6.8 Hz, 2H), 2.75-2.49 (m, 2H), 1.97-1.85 and 1.78-1.66 (2×m, 1H), 1.51 (d, J=6.9 Hz, 6H), 1.15 and 1.14 (2×d, J=6.9 Hz, 3H), 0.90 and 0.87 (2×d, J=6.8 Hz, 3H), 0.79 and 0.74 (2×d, J=6.3 Hz, 3H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])OC1C1C=CC(OC)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][Cl:34].O1CCCC1.S([O-])(O)(=O)=O.[K+]>CCCCCC>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14](=[O:23])[CH2:33][Cl:34])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCBr
Reactant: COc1ccc(C2OC(=O)[C@H](Cc3ccccc3)N2C(=O)OCc2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.55 h
Yield: 62 %

Procedure:
(4S)-N-benzyloxycarbonyl-2-(p-methoxyphenyl)-4-phenylmethyloxazolidin-5-one (Tetrahedron Lett. 1995, 36, 42, 7761) (700 mg) and bromochloromethane (0.142 ml) were added to dehydrated tetrahydrofuran (16.8 ml), and they were cooled to −78° C. 1.54 Mn-butyllithium solution (1.42 ml) in hexane was added to the obtained mixture, and they were stirred for 33 minutes. 5% aqueous potassium hydrogensulfate solution was added to the reaction mixture to terminate the reaction. After the extraction with ethyl acetate at room temperature twice followed by drying over anhydrous magnesium sulfate, magnesium sulfate was removed. The obtained solution in ethyl acetate was analyzed by HPLC to find that (3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (347 mg) was obtained in a yield of 62%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].F[C:25]1[CH:30]=[C:29](F)[C:28]([F:32])=[CH:27][C:26]=1[S:33]([CH:36]1[CH2:40][CH2:39][O:38]C1=O)(=[O:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:32][C:28]1[C:29]([O:1][C:2]2[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=2)[C:5]([NH:7][C:8]2[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[O:6])=[CH:30][C:25]2[O:38][CH2:39][CH2:40][CH2:36][S:33](=[O:35])(=[O:34])[C:26]=2[CH:27]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Reactant: O=C1OCCC1S(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cc3c(cc2F)S(=O)(=O)CCCO3)cc(C(=O)Nc2cnc(C)cn2)c1
Yield: 14.3 %

Procedure:
3-Hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (634 mg, 2 mmol), 3-[(2,4,5-trifluorophenyl)sulfonyl]dihydrofuran-2(3H)-one (560 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol) in acetonitrile (10 mL) were heated at 160° C. for 2 h and 170° C. for 30 minutes in a microwave reactor. Water was added to the reaction mixture and the phases separated. The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organics washed with 1M hydrochloric acid, a saturated sodium bicarbonate solution, brine and dried (MgSO4) and evaporated. The residue was dissolved in methanol and heated to reflux on a steam bath. The residual solid was removed by hot filtration and the filtrate evaporated to a residue which was chromatographed on alumina, eluting with 10% methanol in DCM, to give the desired compound as a clear foam (152 mg). 1H NMR δ (CDCl3): 1.27 (d, 3H), 2.32-2.38 (m, 2H), 2.49 (s, 3H), 3.31 (t, 2H), 3.34 (s, 3H), 3.43-3.47 (m, 1H), 3.49-3.54 (m, 1H), 4.15 (t, 2H), 4.53-4.57 (m, 1H), 6.72 (d, 1H), 6.77 (t, 1H), 7.08 (t, 1H), 7.25 (t, 1H), 7.71-7.74 (m, 1H), 8.07 (d, 1H), 8.25 (s, 1H), 9.45 (d, 1H); m/z 532 (M+H)+, 530 (M−H)−
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].Cl.Cl.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(CN=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and a solution of p-(dimethylamino)benzylamine dihydrochloride (0.65 g, 2.9 mmol) and triethylamine (0.64 g, 6.4 mmol) in methanol (5 ml) were added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was extracted with ethyl acetate (50 ml×3). The ethyl acetate layer was washed with water (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroformmethanol (100:1). The eluted fractions were concentrated under reduced pressure and then crystallized from methanol-diethyl ether to give the title compound (0.63 g, 2.3 mmol, yield: 85%) as colorless powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[N:10][C:9]([C:12]([O:14]CC3CC3)=[O:13])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C1COCC1.[OH-].[Li+].Cl>CO>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[N:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(OCC1CC1)c1ccc(OCC2CC2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
To a solution of cyclopropylmethyl 6-(cyclopropylmethoxy)pyridazine-3-carboxylate (0.48 g) in a mixed solvent of THF (5 mL) and methanol (5 mL) was added 1 M aqueous lithium hydroxide solution (5 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.40 g).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C(N(CC)CC)C>>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCNCC1c1ccc([N+](=O)[O-])cn1
Reaction time: 18 h
Yield: 101 %

Procedure:
A mixture of tert-butyl 1-piperazinecarboxylate (1.0 g, 5.3 mmol), 2-chloro-5-nitropyridine (0.85 g, 5.3 mmol) and triethylamine (1.58 mL, 11.0 mmol) in CH3 -CN (50 mL)were stirred at rm temperature for 18 hr. The yellow suspension was concentrated, the residue was taken up in CH2Cl2 (125 mL) and washed with 5% NaHCO3 (2×25 mL) and brine (2×25 mL), dried over MgSO4 and concentrated to dryness in vacuo to yield the yellow titled compound (1.65 g, 100%). MS (ES) m/e 309.2 [m+H]+ 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[Si:19]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 79 g of 3-(hydroxymethyl)phenol in 300 mL of DMF cooled at 0° C. was added 50 g of imidazole followed by 101 g of tert-butyl(chloro)dimethylsilane. The reaction was warmed to rt and stirred overnight. The reaction was quenched with aqueous NH4Cl, extracted with EtOAc and washed with brine, dried over sodium sulfate, evaporated, and purified by flash chromatography (10–30% EtOAc/hexane) to afford 140 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N: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]=[C:30]([CH3:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH3:35])[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[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH3:35])[N:27]=2)[CH:6]=1
Reactant: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(4-methyl-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (91 mg, 188 μmol) in dichloromethane (2.9 mL) was added trifluoroacetic acid (429 mg, 290 μL, 3.76 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo then diluted with NH4OH and dichloromethane. The mixture was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica, 3 to 15% methanol in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (46 mg, 120 μmol, 64%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (s, 1H), 8.34 (s, 1H), 8.08 (s, 1H), 7.63 (s, 1H), 6.80 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 6.60 (s, 1H), 3.88 (s, 1H), 3.25 (s, 1H), 2.67 (t, J=7.4 Hz, 1H), 2.26 (s, 3H), 1.71 (m, 2H), 1.54-1.71 (m, 6H), 1.35 (s, 2H), 0.93 (t, J=7.2 Hz, 3H); MS (EI/CI) m/z: 384.1 [M+H].
Reaction SMILES: CO[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[NH:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12]>C1COCC1>[F:7][C:4]([F:5])([F:6])[C:3]([N:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12])=[O:8]
Reactant: COC(=O)C(F)(F)F
Reactant: OCCNCCO
Solvent: C1CCOC1
Product: O=C(N(CCO)CCO)C(F)(F)F
Temperature: 25 °C

Procedure:
Methyltrifluoroacetate (25 g, 195.3 mmol) was added drop wise to an ice cooled stirred solution of 2,2′-iminodiethanol (20.5 g, 195 mmol) in anhydrous THF (100 mL). The reaction mixture was allowed to warm to ambient temperature naturally and stirred over night at ambient temperature. The solvent was evaporated via rotary evaporation to yield the title compound as a clear oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>CN(C=O)C>[CH3:34][S:35]([N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(-c2nc(-c3cccc4c3ccn4S(C)(=O)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (80 mg) in DMF (0.80 ml) was added 60% NaH (8.7 mg) at 0° C., followed by stirring at room temperature for 0.5 hour. Methanesulfonyl chloride (21.1 μl) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The filtrate was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 98:2) to obtain 1-(methylsulfonyl)-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (15.6 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=O)(=[O:10])=[O:9])[CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:13](=[O:15])[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[S:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:10]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Reactant: NCc1cccc(F)c1
Product: O=C(NCc1cccc(F)c1)c1ccccc1S(=O)(=O)Nc1cccnc1
Yield: 84 %

Procedure:
The title compound was prepared according to procedures described above, using methyl 2-[(pyridin-3-ylamino)sulfonyl]benzoate and 3-fluorobenzylamine. The title compound was further purified by dissolving 25 g in EtOH (300 mL) and gently heating using water bath to 80° C. The resulting solids material were then slowly dissolved and more EtOH (50 mL) was added to completely dissolve all the solids. The solution left at room temperature to crystallize for 1 h. The resulting crystals were collected and dried under high vacuum for 16 h to afford the title compound as a crystalline solid (21 g, 84%). 1H NMR (400 MHz, DMSO-D6) δ 9.76 (s, 1H) 9.32 (t, 1H) 8.31 (d, 1H) 8.25 (d, 1H) 7.66-7.78 (m, 2H) 7.50-7.65 (m, 3H) 7.39 (q, 1H) 7.23-7.29 (m, 3H) 7.09 (t, 1H) 4.54 (d, 2H).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Ti+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(N(CC)CC)C>CCOCC>[Cl-:1].[Cl-:1].[CH:4]1([Ti+2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: Oc1ccccn1
Reactant: [Ti+3]C1C=CC=C1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C1=CC([Ti+2]Oc2ccccn2)C=C1
Reaction time: 8 h

Procedure:
To a solution of 0.002 moles of cyclopentadienyl titanium trichloride in 50 mL of ether a solution of 2-hydroxy pyridine (0.002 moles) and triethylamine (0.002 moles) in 50 mL of ether was added at 0° C. and stirred overnight. The product was recovered from the ether filtrate. The product has the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: C1COCCN1
Product: COc1cccc2cc(C(=O)N3CCOCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and morpholine to give 7-methoxy-2-morpholinocarbonylbenzofuran (Compound 329a). Successively, it was formylated to give 4-formyl-7-methoxy-2-morpholinocarbonylbenzofuran (Compound 329b), then compound 329b was reacted with methylamine hydrochloride to give compound 329 as a white solid.