Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:33]C)[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].CNCC[OH:39]>>[OH:39][CH2:2][CH2:1][N:3]([CH3:33])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7]
Reactant: CNCCO
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: CN(CCO)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 80.2 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (400 mg) obtained in Example 6 (4) and N-methylethanolamine (140 mg). This was purified by silica gel column chromatography to give the title compound (322 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reaction time: 5 h
Yield: 91.3 %

Procedure:
A mixture of 3.0 g 1-bromo-4-methylsulfonyl benzene, 3.3 g piperazine and 470 mg tetrabutyl ammonium iodide was stirred at 120° C. to 140° C. for 5 hours. Water was added to the mixture, then insolubles were filtered off, the filtrate was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography, to give 2.8 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH:33]([CH3:35])[CH3:34])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH:33]([CH3:35])[CH3:34])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:37]([CH3:36])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CC(C)c1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CC(C)c1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 24.9 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(cyclohexyl{2-isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzoic acid (195 mg) as well as ethyl 3-(methylamino)propanoate (63 mg) to give the title compound (57 mg, 25%) as an amorphous compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([C:18]2[C:19](=[O:32])[N:20]([CH2:29][CH2:30][CH3:31])[C:21](=[O:28])[N:22]3[CH2:27][CH:26]=[CH:25][S:24][C:23]=23)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[O:9]=[S:24]1[CH2:25][CH:26]=[CH:27][N:22]2[C:21](=[O:28])[N:20]([CH2:29][CH2:30][CH3:31])[C:19](=[O:32])[C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:23]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CC=CS2
Solvent: ClCCl
Product: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)C=CCS2=O
Yield: 84.2 %

Procedure:
m-Chloroperbenzoic acid (0.34 g)was added to a solution of 9-phenyl-7-propyl-4H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (0.53 g) in methylene chloride (10 mll) little by little with stirring under ice cooling, and then, the reaction mixture was stirred at room temperature for 10 hours. An insoluble material was removed by filtration, and the filtrate was washed with a saturated aqueous sodium bicarbonate. After drying, the organic solution was concentrated to dryness. The resulting residue was purified column chromatography on silica gel. The resulting crude crystals were recrystalized from methylene chloride-isopropyl ether to give colorless needles (0.47 g, 87%).
Reaction SMILES: N[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N[C@@H](C(O)=[O:29])CC1C2C(=CC=CC=2)NC=1.NC(C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C:2](=[O:29])[C:13]([OH:15])=[O:14])=[CH:5]1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)C(=O)Cc1c[nH]c2ccccc12

Procedure:
The “amino acid oxidase activity” for reaction 1 means an activity catalyzing the reaction shown in scheme (13). Generally, L-amino acid oxidase generates keto acid from the corresponding L-amino acid, while D-amino acid oxidase generates keto acid from the corresponding D-amino acid. Specifically, in accordance with the present invention, individually, a microorganism having L-amino acid oxidase activity may be used when L-tryptophan is used as the raw material, while a microorganism having D-amino acid oxidase activity may used when D-tryptophan is used as the raw material. Additionally, the preparation from DL-tryptophan is also applicable. When D- and L-amino acid oxidase is allowed to interact with DL-tryptophan, the intended indole-3-pyruvic acid may be quantitatively produced. When D- or L-amino acid oxidase interacts with DL-tryptophan, otherwise, the intended indole-3-pyruvic acid may be produced at a yield of 50%.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11]O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P(Br)(Br)[Br:30]>C1COCC1>[Br:30][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:6]=[C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])[N:4]=2
Reactant: BrP(Br)Br
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1

Procedure:
To crude (9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methanol (6 g) in anhydrous THF (400 mL) was added phosphorus tribromide (2.7 mL). The reaction was monitored by LC/MS until complete. The heterogeneous reaction mixture was passed thru a Buchner funnel and the solid was collected and rinsed with thrice with water and twice with MeOH to get 2 g of crude 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine of which 50 mg was reacted with bicyclo[2.2.2]octan-1-amine (1-adamantyl amine) via General Procedure E to give 5.7 mg of 270 following reverse phase purification. MS (Q1) 513.3 (M)+
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][N:30]([CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH2:31]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc(COc2cccc3c2CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3c(cccc3OCc3ccccc3)C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A suspension of 0.098 g (0.00051 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 2 ml of dimethylformamide was treated with 0.21 ml (0.0015 mol) of triethylamine and 0.145 g (0.00061 mol) of 5-benzyloxy-1,2,3,4-tetrahydro-isoquinoline (WO 94/20459) and the mixture was stirred at room temperature under argon for 18 hours The solvent was distilled off in a high vacuum. The residue was partitioned between dichloro-methane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.153 g (84%) of 5-(5-benzyloxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as a yellowish oil. MS (ISP): me/e=361 (C22 H25N4O+).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>[Ti](Cl)(Cl)(Cl)Cl.CCOCC>[Cl:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:5]=1[C@@H:6]([OH:7])[CH3:1]
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: [Li]C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: C[C@H](O)c1cccc([N+](=O)[O-])c1Cl
Temperature: -40 °C
Yield: 84 %

Procedure:
To ether cooled to −78° C. was added titanium (IV) chloride (0.85 mL, 7.8 mmol) and a 1.6M solution of methyl lithium in ether (4.9 ml, 7.8 mmol). After warming the mixture to −40° C., it was transferred via double-tipped needle to a −78° C. ether solution of 2-chloro-3-nitrobenzaldehyde (1.0 g, 5.6 mmol), which can be synthesized according to the procedure in J. Med. Chem. 1088, 31, 936-944. The reaction was allowed to slowly warm to rt and was quenched with the addition of MeOH and water. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated to an oil. The crude material was purified by flash column chromatography (10% EtOAc:hexanes) to give 0.98 g of the racemic compound (84%). The enantiomers were separated using packed column supercritical fluid chromatography (SFC) on a 3×25 cm Dalcel® AD-H column with a 90 g/min total flow (81 q/min CO2-90%) (9 g/min MeOH-10%) to give the title compound as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 7.86 (m, 1H), 7.58 (m, 1H), 5.62 (d, J=4.4 Hz, 1H), 5.06 (m, 1H), 1.30 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]2[C:12](=O)[NH:11][C:10]([O:14][CH3:15])=[N:9][S:8]2(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>P(Cl)(Cl)(Cl)=O>[Cl:19][C:12]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[S:8](=[O:17])(=[O:16])[N:9]=[C:10]([O:14][CH3:15])[N:11]=1
Reactant: COC1=NS(=O)(=O)N(C2CCCCC2)C(=O)N1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC1=NS(=O)(=O)N(C2CCCCC2)C(Cl)=N1

Procedure:
A mixture of the thiatriazinone from Step 2. above (77.3 g) and phosphorus pentachloride (92.4 g) in phosphorus oxychloride (230 ml) is refluxed overnight. The reaction mixture is evaporated at 50° C. yielding an oil (92.3 g) which is used without further purification in the next step.
Reaction SMILES: N1CCCCC1.[H-].[Na+].[CH2:9]([O:16][C:17]1[C:18]2[N:19]3[C:23](=[CH:24][CH:25]=1)[C:22]([CH2:26][CH3:27])=[C:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=1)[C:20]3=[C:42]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49]Cl)[CH:43]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C>CN(C)C=O.O>[CH2:9]([O:16][C:17]1[C:18]2[N:19]3[C:23](=[CH:24][CH:25]=1)[C:22]([CH2:26][CH3:27])=[C:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:30][CH:29]=1)[C:20]3=[C:42]([CH2:44][O:45][CH2:46][CH2:47][CH:48]=[CH2:49])[CH:43]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCl)cc3c(OCc4ccccc4)ccc1n32
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCOCc1cc2c(OCc3ccccc3)ccc3c(CC)c(-c4ccc(OCc5ccccc5)cc4)c1n23
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Piperidine (0.14 g, 1.22 mmol) was dissolved in 50 ml of dry dimethylformamide under a nitrogen atmosphere and sodium hydride (60% in oil) (47 mg, 1.16 mmol) was added. The mixture was stirred for 1/2 hour. 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-((4-chlorobutoxy)methyl)-1-ethylpyrrolo[2,1,5-cd ]indolizine (0.337 g, 0.583 mmol) was added and the mixture was stirred at 55-64° for 7 days. Ethanol (10 ml) was added dropwise, and the reaction mixture was diluted with 250 ml of water. The organic material was extracted into ethyl acetate (3×100 ml), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using 5% of methanol in dichloromethane as the eluent. Fractions contaiing the product wre collected to afford 165 mg (52%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-((but-3-enyloxy)methyl)-1-ethylpyrrolo[2,1,5-cd ]indolizine as an oil. MS(SP): m/z 541 (M+). 1H-NMR (DMSO-d6, 300 MHz) δ: 1.33 (t, 3H); 2.18 (m, 2H); 3.05 (q, 2H); 3.43 (t, 2H); 4.71 (s, 2H); 4.93-5.07 (m, 2H); 5.19 (s, 2H); 5.58 (s, 2H); 5.72 (m, 1H); 7.18 (d, 2H); 7.30-7.62 (m, 14H); 7.98 (d, 1H).
Reaction SMILES: CC(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([O:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]#[N:26])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)(C)C>Cl.O1CCOCC1>[ClH:24].[NH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[O:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]#[N:26]
Reactant: CC(C)(C)OC(=O)NCCCC(Oc1cc(Cl)ccc1C#N)c1nccs1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(Cl)cc1OC(CCCN)c1nccs1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
The product from step (d) (0.20 g) was dissolved in 4M hydrochloric acid in dioxan (5 ml) and stirred for 3hat room temperature. The solvent was evaporated and the residue triturated with dry diethyl ether to give the title compound as a pale yellow solid (0.055 g). M.p 170-172° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]=[O:23])[CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][OH:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To [3-(4-chloro-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.9 g, 2.6 mmol) in MeOH (30 mL) was added sodium borohydride (0.11 g, 2.9 mmol), and the mixture was stirred at room temperature for 10 minutes. The mixture was worked-up to give the title compound.
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:10]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:29][C:30]1[CH:31]=[C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:45][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]3)[O:39][N:38]=2)[CH:33]=[CH:34][C:35]=1[CH3:36]>ClCCl.N1C=CC=CC=1>[CH3:36][C:35]1[CH:34]=[CH:33][C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:43][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:45]3)[O:39][N:38]=2)=[CH:31][C:30]=1[NH:29][C:14]([C:11]1[N:9]2[CH:10]=[C:5]([CH2:4][CH2:3][C:2](=[O:1])[CH3:17])[CH:6]=[CH:7][C:8]2=[N:13][CH:12]=1)=[O:16]
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Reactant: CC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCC(C)=O)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (78) (50 mg, 0.215 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (20 uL, 0.237 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated and the crude solid was dried under vacuo. Next, methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (27 mg, 0.0796 mmol) and anhydrous pyridine (1 mL) were added to the acid chloride. The reaction was stirred to room temperature under Argon for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(4-methyl-3-(6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F65). 1H NMR (400 MHz, d6-DMSO) δ 10.02 (s, 1H), 9.31 (s, 1H), 8.55 (s, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.83 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.46 (dd, J=1.6, 9.2 Hz, 1H), 4.39-4.34 (m, 2H), 4.31-4.25 (m, 1H), 4.22-4.18 (m, 2H), 3.59 (s, 3H), 2.85 (s, 4H), 2.37 (s, 3H), 2.10 (s, 3H). MS m/z 503.2 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9](Br)[CH2:8][CH2:7]1.Cl[SiH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.Cl[SiH]1CCC(C2C=CC(F)=C(F)C=2)CC1>>[F:1][CH:2]([F:13])[CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([Si@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH2:8][CH2:7]1
Reactant: FC(F)CCCC1CCC(Br)CC1
Reactant: Fc1ccc(C2CC[SiH](Cl)CC2)cc1
Agent: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Product: Fc1ccc([C@H]2CC[Si@H]([C@H]3CC[C@H](CCCC(F)F)CC3)CC2)cc1

Procedure:
The above compound was obtained in the same manner as Example 6, using 4-(4, 4-difluorobutyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-fluorobenzene instead of 4-(4-fluorobutyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-l, 2-difluorobenzene, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:40]=[CH:39][C:35]2[O:36][CH2:37][O:38][C:34]=2[CH:33]=1>>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([CH2:31][O:1][C:2]3[CH:3]=[C:4]([C:8]4[C:17]5[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=5)[N:11]=[CH:10][C:9]=4[C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:23])[CH:5]=[CH:6][CH:7]=3)=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc3c(c2)OCO3)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 5-Bromomethyl-benzo[1,3]dioxole following the procedure of Example 478: MS (ESI) m/z 528; HRMS: calcd for C31H20F3NO4+H+, 528.14172; found (ESI, [M+H]+), 528.1435.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[C:25]([CH2:27]Br)[CH:24]=[CH:23][N:22]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])[CH:26]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)OCC
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
To a solution of NaH (80%, 0.17 g, 4.00 mmol) in THF (5 mL) at 0° C. under argon was added diethyl malonate (0.64 g, 4.00 mmol). After the mixture was stirred for 15 min the mixture was added to a refluxed mixture of (4-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.00 g, 3.48 mmol) in THF (10 mL), and the mixture was refluxed for 2 h. The mixture was concentrated under reduced pressure and the residue was partitioned between water and chloroform. The organic layer was washed with water and brine and dried. After filtration and evaporation of the solvent, the crude product was purified by flash chromatography (MeOH/CH2Cl2, 1:100) to give 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-malonic acid diethyl ester (0.80 g, 55%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[CH2:17]([Li])CCC>C1COCC1.CCOCC>[CH3:17][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]
Reactant: Nc1ccccc1-c1nc2ccccc2[nH]1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(1H-benzo[d]imidazol-2-yl)benzenamine (525 mg, 2.5 mmol) in 5 mL dry THF was cooled to −78 degrees before 1 mL n-Bu-Li (2.5 mmol, 2.5 N in hexanes) was added via a syringe. The reaction was stirred at −78 degrees for 20 min and Mel (360 mg, 2.6 mmol) was added. The reaction was warmed to r.t. gradually and kept at room temperature for another hour. The reaction crude was diluted with 25 mL ether and the resulted suspension was filtered off the solid. The crude product was isolated after the solvent was removed from the collected filtrate to product 510 mg of 2-(1-methyl-1H-benzo[d]imidazol-2-yl)benzenamine in greater than 95% purity (MS, M++H=224.1).
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Cl[C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1.Cl>C1(C)C=CC=CC=1.O>[CH2:1]([S:13][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCCCCCCCCCCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCSc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 40.5 g (0.2 mole) of 1-dodecanethiol (laurylmercaptan) in 19.2 g (0.4 mole) of sodium hydride (50% in oil) in 1 liter of toluene is refluxed with stirring for 1 hour then cooled to room temperature. To the mixture 32.5 g (0.2 mole) of 5-chloro-2-thiophenecarboxylic acid is added and the mixture is refluxed with stirring for 24 hours after which the mixture is cooled to room temperature and acidified with 5% aqueous hydrochloric acid. Water is added, and the toluene layer is separated, dried over sodium sulfate and evaporated to give 5-(dodecylthio)-2-thiophenecarboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].CCO[C:29]([CH3:31])=[O:30]>CN1C(=O)CCC1>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[C@@H:11]([C:8]1[N:6]2[N:7]=[C:2]([N:10]3[CH2:9][CH2:8][N:6]([CH3:5])[C:29](=[O:30])[CH2:31]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CCOC(C)=O
Reactant: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
6-Chloro-3-[(S)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate E, 50.0 mg, 0.152 mmol), KF (26.4 mg, 0.455 mmol) and 1-methylperazine-2-one hydrochloride (51.9 mg, 0.455 mmol) were suspended in NMP (1 mL). The RM was stirred at 180° C. for 5 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 3.66 min (conditions 5), (tR 12.22 min (conditions 2), MH+=408.2, 1H-NMR in DMSO-d6: 7.92 (s, 1H); 7.83 (d, 1H); 7.49 (m, 3H); 7.11 (d, 1H); 4.78 (m, 1H); 4.00 (d, 1H); 3.95 (s, 3H); 3.86 (d, 1H); 3.67 (m, 2H); 3.30 (m, 2H); 2.80 (s, 3H); 1.71 (d, 3H)).