Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]([CH2:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]([CH2:16][O:17][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Subsequently, to a solution of [(1S)-1-(hydroxymethyl)-3-methylbutyl]carbamic acid benzyl ester (4.84 g, 19.3 mmol) in dimethylformamide (145 ml) were added t-butyldiphenylsilyl chloride (6.01 ml, 23.1 mmol) and imidazole (1.57 g, 23.1 mmol) in an ice bath, and then the mixture was stirred at room temperature for 8 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (19:1→7:1) as the eluant to afford [(1S)-1-(t-butyldiphenylsilyloxymethyl)-3-methylbutyl]carbamic acid benzyl ester (9.22 g, yield 98%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][C:19]=1[CH3:27].Cl>C(OC)(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:25][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[C:19]([CH3:27])[CH:20]=1)=[O:26]
Reactant: CC(=O)c1ccc(-c2ccco2)c(C)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Reaction time: 20 h

Procedure:
To a stirred soluition of ethyl trifluoroacetate (0.66 g, 4.67 mmol) in t-butylmethylether (15 mL) was added sodium methoxide (28 wt. % solution in methanol; 1.2 mL, 4.98 mmol) over 2 min. A solution of 1-[4-(2-furyl)-3-methylphenyl]ethanone in t-butylmethylether (4 mL) was added dropwise over 5 minutes, and the mixture was stirred for 20 hours. 2N HCl (10 mL) was added, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 1.12 g of brown oil. The compound was used for next reaction without purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C1CCNCC1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with piperidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-piperidin-1-yl-butoxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 505 (MH+).
Reaction SMILES: CC[O-].[Na+].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:6][SH:7].Br[C:13]1[N:14]=[C:15]([CH3:28])[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17]=1[CH:18]=O.CCCCCC>C(O)C>[CH3:28][C:15]1[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:17]2[CH:18]=[C:6]([C:5]([O:9][CH2:10][CH3:11])=[O:8])[S:7][C:13]=2[N:14]=1
Reactant: CCOC(=O)CS
Reactant: Cc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)c1cc2c(nc(C)n2COCC[Si](C)(C)C)s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.68 M Sodium ethylate was dissolved in ethanol (50 ml) and a solution (25 ml) of ethyl thioglycolate in ethanol was added. Thereto was added a solution (150 ml) of 4-bromo-2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)imidazol-5-carboxaldehyde (3.16 g) in ethanol and the mixture was stirred at 80° C. for 2 hr. The solvent was evaporated under reduced pressure and water was added. The mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was obtained by silica gel column chromatograhy (hexane/ethyl acetate=9/1). Hexane was added to the purified product and crystals were collected by filtration to give the objective compound (765 mg) as pale-brown crystals.
Reaction SMILES: [C:1]([C:3]1([CH2:14]O)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].CCN(S(F)(F)[F:22])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1([CH2:14][F:22])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(CO)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C#N)(CF)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate (5.0 g) was dissolved in DCM (100 mL). At 0° C., DAST (3.74 mL) was added thereto, followed by stirring at 0° C. for 3 hours. Three hours later, to the reaction liquid was added an aqueous NaHCO3 solution (100 mL), followed by extraction with DCM (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 50:50) to obtain tert-butyl 3-cyano-3-(fluoromethyl)azetidine-1-carboxylate (1.24 g) as a brown solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[C:32]([C:36]1[O:37][CH:38]=[C:39](/[CH:41]=[CH:42]/[C:43]2[C:44]([OH:54])=[N:45][N:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:47]=2)[N:40]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([C:36]1[O:37][CH:38]=[C:39](/[CH:41]=[CH:42]/[C:43]2[C:44]([O:54][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:45][N:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:47]=2)[N:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CC(C)(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 20.4 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.29 g), 4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (1.24 g), potassium carbonate (0.995 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to aminopropyl silica gel column chromatography and eluted with ethyl acetate-hexane (1:5-1:4-1:3, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (430 mg, yield 20%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:20][S:21](O)(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:20][S:21]([O:12][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)O
Reactant: COc1cccc(CC(C)O)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC(C)OS(C)(=O)=O)c1
Yield: 98.2 %

Procedure:
To a cold solution (5° C.) of 1-[3-(methyloxy)phenyl]-2-propanol (1) (75 g, 0.45 mol) in CH2Cl2 (500 mL) were added Et3N (100 mL, 0.72 mol) and DMAP (2.75 g, 22.5 mmol). Methanesulfonic acid (52 mL, 0.675 mol) was added slowly (drop-wise) to the above reaction mixture at that temperature over a period of 40 min. The resultant mixture was stirred between 5° C. and 10° C. for 8 h under N2. The reaction mixture was washed with H2O (3×150 mL), brine (1×100 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the crude product which was passed through a pad of silica to afford 108 g (98%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.24 and 7.20 (dd, J1=15.2 Hz, J2=3.8 Hz, 1H), 6.81-6.76 (m, 3H), 4.87 (sextet, J=6.00 Hz, 1H), 3.77 (s, 3H), 2.96 and 2.92 (dd, J1=14.0 Hz, J2=8.0 Hz, 1H), 2.87 and 2.84 (dd, J1=14.0 Hz, J2=5.6, Hz, 1H), 2.54 (s, 3H), 1.44 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:41])[NH:5][C:6](=[O:40])[N:7]([CH:39]=1)[C@@H:8]1[O:38][C@H:16]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:10](OS(C)(=O)=O)[CH2:9]1)[CH3:2].[I-:42].[Na+]>COCCOC>[I:42][C@@H:10]1[C@@H:16]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:38][C@@H:8]([N:7]2[CH:39]=[C:3]([CH2:1][CH3:2])[C:4](=[O:41])[NH:5][C:6]2=[O:40])[CH2:9]1
Reactant: [I-]
Reactant: CCc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cn([C@H]2C[C@H](I)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-3'-O-methanesulfonyl-5'-O-trityl-2'-deoxyuridine (3.2 g, 5.6 mmole) and sodium iodide (15.0 g, 100 mmole) in 1,2-dimethoxyethane is refluxed for 18 hr.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]=[C:19]4[N:21]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=[C:23]([CH2:24][CH3:25])[C:18]4=[C:17]([O:32][CH3:33])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:3]1.[C:34](OC(N1C(C)CNCC1C)=O)(C)(C)C.Cl>>[CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]=[C:19]4[N:21]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=[C:23]([CH2:24][CH3:25])[C:18]4=[C:17]([O:32][CH2:33][CH3:34])[CH:16]=3)=[CH:13][CH:14]=2)[CH2:3]1
Reactant: CC1CNCC(C)N1C(=O)OC(C)(C)C
Reactant: CCc1nn(-c2ccccc2)c2nc(-c3ccc(N4CC(C)NC(C)C4)cc3)cc(OC)c12
Agent: Cl
Product: CCOc1cc(-c2ccc(N3CC(C)NC(C)C3)cc2)nc2c1c(CC)nn2-c1ccccc1

Procedure:
The title compound was prepared according to the procedure as described in Example 98 reacting 6-(4-bromo-phenyl)-3-ethyl-4-ethoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine (according to Example 98) and 2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Nc1nc(Oc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, phenol and DBU in THF. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([OH:17])=O.[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[O:17])[CH:25]=1)[CH3:19]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)ccc1F
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3)ccc2F)c1

Procedure:
4,4′-Difluoro-biphenyl-3-carboxylic acid (100 mg, 0.43 mmol) was coupled to aniline (60)(82 mg, 0.43 mmol) using Method C to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:36]/[N:35]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@@H:10]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]2)=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(N3CCC(C(=O)O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-{4-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-piperidine-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a yellow foam, MS (ESI−): m/z=456.3 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[OH:29][CH:30]1[CH2:33][NH:32][CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:32]2[CH2:33][CH:30]([OH:29])[CH2:31]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: OC1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: OC1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Synthesized from 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (0.500 g, 1.34 mmol) and 3-hydroxyazetidine hydrochloride (0.293 g, 2.67 mmol) according to the general procedure for reductive amination to afford 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidin-3-ol as a pale yellow solid. MS (ESI) m/z: Calculated: 431.2; Observed: 432.1 (M++1).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:28][CH:29](Br)[CH3:30]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:30][CH2:29][Br:28])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 9-benzyl-9H-Carbazol-4-ol (2.46 g, 9.00 mmol), potassium carbonate (5.11 g, 27.0 mmol), and DMF (10 mL) is added dibromoethane (3.90 mL, 45.0 mmol). The mixture is stirred at 80° C. for 4.5 h and then allowed to cool and stir the remainder of the night. The mixture is then stirred at 85° C.; after about 2 h an additional 1.0 mL of dibromoethane is added. After 5.5 h the mixture is cooled and the solvent and excess dibromoethane are removed in vacuo. The residue is partitioned between Et2O, water, and brine. The organic layers are dried over MgSO4 and taken to dryness. Chromatography on silica gel (250 mL) using EtOAc-heptane (10/90 to 20/80) to give 1.80 g (53%) after crystallization from CH2Cl2-hexane; IR (drift) 1583, 1458, 1446, 1342, 1333, 1281, 1270, 1245, 1154, 1147, 1114, 783, 753, 734, 719 cm−1; 1H NMR (CDCl3) δ3.87, 4.58, 5.51, 6.66, 7.02, 7.12, 7.2-7.4, 8.43. Anal. Calcd for C21H18BrNO: C, 66.33; H, 4.77; N, 3.68; Br, 21.01. Found: C, 66.30; H, 4.76; N, 3.62.
Reaction SMILES: [N+]([O-])([O-])=O.[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([NH2:17])=[NH2+:16])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[C:18]([O:22][C:23]([NH:25][C:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35](=O)[C:36]([C:41]#N)=[CH:37][N:38](C)C)=[CH:31][CH:30]=1)([CH3:28])[CH3:27])=[O:24])([CH3:21])([CH3:20])[CH3:19].[OH-].[Na+]>CC(O)C>[C:18]([O:22][C:23]([NH:25][C:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:37]#[N:38])=[CH:41][N:17]=[C:15]([NH:14][C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[NH:5][N:6]=[CH:7]4)[N:16]=2)=[CH:31][CH:30]=1)([CH3:28])[CH3:27])=[O:24])([CH3:20])([CH3:19])[CH3:21]
Reactant: NC(=[NH2+])Nc1ccc2[nH]ncc2c1
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc4[nH]ncc4c3)ncc2C#N)cc1
Yield: 90.5 %

Procedure:
A mixture of indazol-5-ylguanidinium nitrate (524 mg, 2.2 mmol), 1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropen-1-one (714 mg, 2.0 mmol) and powdered sodium hydroxide (96 mg, 2.4 mmol) in propan-2-ol (30 ml) was heated at reflux for 6 h. The reaction was concentrated in vacuo and the residue purified by column chromatography (silica, 60% ethyl acetate in hexane, loading the crude material in dichloromethane) to give 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)-pyrimidine-2-amine as a yellow solid (850 mg). δH (CDCl3) 8.69 (1H, s), 8.18 (1H, s), 8.11 (1H, s), 8.05 (2H, d, J 8.4 Hz), 7.93 (1H, bs), 7.57 (2H, d, J 8.4 Hz), 7.50 (2H, m), 5.10 (1H, bs), 1.66 (6H, s), 1.40 (9H, bs). MS (ESI) 492 (MNa+, 61%), 470 (MH+, 100%), 414 (19%). This product was dissolved in a mixture of TFA acid (20 ml) and CH2Cl2 (20 ml) and was stirred for 30 mins at room temperature before concentrating the reaction in vacuo. The residue was dissolved in 10% MeOH in CH2Cl2 (200 ml) and the organic phase washed with sat. Na2CO3 (aq) (50 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a bright yellow solid (541 mg) m.p. 267-271° (dec.). δH (d6DMSO) 13.03 (1H, bs), 10.46 (1H, s), 8.91 (1H, s), 8.16 (1H, s), 8.04 (1H, s), 7.94 (2H, d, J 8.4 Hz), 7.74 (2H, d, J 8.4 Hz), 7.61 (1H, m), 7.52 (1H, d, J 8.9 Hz), 3.44 (2H, bs), 1.48 (6H, s). MS (ESI) 392 (MNa+, 11%), 370 (MH+, 23%), 353 (100%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:16]Br>C(Cl)Cl>[Br:16][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)Cc1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Ethyl 4-acetyl-phenylacetate from Example 25 Part A (489 mg, 2.4 mmol) was dissolved in CH2Cl2. Bromine (379 mg, 2.4 mmol) was added dropwise. The reaction was stirred at rt for 16 h. The reaction had decolorized from rust red to light yellow. The solvent was evaporated in vacuo to yield 680 mg (99%) of ethyl 2-(4-(2-bromoacetyl)phenyl)acetate as a light yellow oil. The product was used in the next step without further purification. MS 287.0 and 289.0 of equal intensities (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[OH:20][C:21]1[CH:22]=[C:23](OB(O)O)[CH:24]=[CH:25][CH:26]=1>>[OH:20][C:21]1[CH:26]=[C:25]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)Oc1cccc(O)c1
Product: O=C1CCCc2cc(-c3cccc(O)c3)ccc21
Reaction time: 4 h
Yield: 29 %

Procedure:
The compound is prepared by the reaction of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-yl trifluoromethanesulfonate (1.78 g, 6.04 mmol, 1 eq) with 3-hydroxyphenylboric acid (1 g, 7.25 mmol, 1.2 eq) according to method A within 4 h. Purification by column chromatography with dichloromethane as the eluent yields the desired product in a yield of 29%, 900 mg.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(O)cc1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: COc1ccc(Oc2nnc(N)nc2-c2ccccc2)cc1
Yield: 12.8 %

Procedure:
6-(4-Methoxyphenoxy)-5-phenyl-1,2,4-triazin-3-amine (45 mg, 13%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 4-methoxyphenol (0.30 g, 2.39 mmol) according to the general procedure of Example 3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH2:15])([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCOCC1.[OH-].[Na+].C(O)(C(F)(F)F)=O>[CH2:20]([O:19][C:17](=[O:18])[NH:15][C:11]1([CH3:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC1(NC(=O)OCc2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
4-Amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester 80E (4.19 g, 19.6 mMol) was dissolved in a solution of 50 mL of dioxane and 20 mL of aqueous 2 N NaOH under an atmosphere of dry N2. To this solution was slowly added benzyl chloroformate (5.6 mL, 39 mMol) and the reaction was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated under vacuum. The reaction mixture was dissolved in DCM and successively washed three with aqueous 1 N NaOH. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a yellow oil. The oil was dissolved in 15 mL of TFA under an atmosphere of dry N2. The reaction mixture was concentrated under vacuum and partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give 3.06 g of an oil. The oil was chromatographed on flash silica gel eluting with DCM to remove less polar impurities then with MeOH/DCM/NH4OH (20179.90.1) to give 2.85 g of the title compound 80F as an oil.