Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].CCOCC.[N+:17]([O-])([OH:19])=[O:18]>O>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]=1[N+:17]([O-:19])=[O:18]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1c(O)ccc2c1CCCC2
Reaction time: 1 h
Yield: 32.6 %

Procedure:
5,6,7,8-Tetrahydro-2-naphthol (50 g, 0.337 mol) was mixed with ether (400 ml), and the mixture was added dropwise with 60% nitric acid (28 ml, 0.368 mol) while the reaction temperature was kept below 15° C. , and then stirring was continued at 15° to 20° C. for 1 hour. The reaction mixture was added with water (500 ml) and extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 900 g, eluent: hexane/ethyl acetate=50/1 to 60/1) to give 2-hydroxy-5,6,7,8-tetrahydro-1-nitronaphthalene (21.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.[CH2:13]1COCC1.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([O:10][CH3:13])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: C1CCOC1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C[C@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-((R)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (15.8 g, 90.9 mmol) in a 3:1 mixture of THF:MeOH (100 mL) was cooled in an ice bath. After adding 2.0 M TMSCHN2 (50 mL, 100 mmol) the bath was removed, and the mixture was stirred at room temperature for 3 h. The solvent was evaporated, and the crude material was purified via silica gel chromatography using 0-50% EtOAc/hexanes to give methyl 2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate. 1H NMR (400 MHz, CDCl3) δ 4.73 (dd, J=6.6, 3.8 Hz, 1H), 3.74 (s, 3H), 2.95 (dd, J=17.0, 3.9 Hz, 1H), 2.81 (dd, J=17.0, 6.6 Hz, 1H), 1.63 (s, 3H), 1.57 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=2)[CH:11]=1)#[N:16]
Reactant: CS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: CS(=O)(=O)c1cncc(C#Cc2cc(C#N)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 5-bromo-3-methylsulfonylpyridine (Combiblocks), the title compound was obtained as a yellow solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:51]=[CH:52][CH:53]=1)[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH:19]2[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][CH2:42][N:41]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]=3[CH:50]=2)=[CH:14][CH:13]=1)=O)C.[NH3:54]>O1CCCC1>[C:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:51]=[CH:52][CH:53]=1)[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH:19]2[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][CH2:42][N:41]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]=3[CH:50]=2)=[CH:14][CH:13]=1)(=[O:3])[NH2:54]
Reactant: CCOC(=O)Cc1cccc(OCc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3OCc3ccc4c(c3)N(CCCOC)CCO4)cc2)c1
Reactant: N
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4cccc(CC(N)=O)c4)cc3)cc21

Procedure:
A solution of 0.114 g of benzyl 4-[4-(3-ethoxycarbonylmethylphenoxymethyl)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 348b), 5 ml of ammonia (7N in methanol) and 1 ml tetrahydrofuran is stirred in a Supelco bottle at 80° C. for 50 hours. After concentration by evaporation, the title compound is obtained as a yellow oil. Rt=4.96.
Reaction SMILES: C[N@+]1(CCC[O:32][C:33](/[C:35](/[Cl:70])=[CH:36]/[C:37]([O:39]CCC[N@+]2(C)[C@@H](C3C=C(OC)C(OC)=C(OC)C=3)C3C=C(OC)C(OC)=CC=3CC2)=[O:38])=[O:34])[C@H](CC2C=C(OC)C(OC)=C(OC)C=2)C2C(=CC(OC)=C(OC)C=2)CC1.Cl/C(=C\C([O-])=O)/C([O-])=O.C(N(CC)CC)C>C(#N)C>[Cl:70]/[C:35](=[CH:36]\[C:37]([OH:39])=[O:38])/[C:33]([OH:34])=[O:32]
Reactant: COc1cc2c(cc1OC)[C@H](c1cc(OC)c(OC)c(OC)c1)[N@@+](C)(CCCOC(=O)/C=C(\Cl)C(=O)OCCC[N@+]1(C)CCc3cc(OC)c(OC)cc3[C@H]1Cc1cc(OC)c(OC)c(OC)c1)CC2
Agent: O=C([O-])/C=C(\Cl)C(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)/C=C(\Cl)C(=O)O

Procedure:
Gantacurium, an asymmetrical chlorofumarate, was prepared in four chemical transformations from compound (XIIIB) using minor modifications of previously reported chemistry, see WO2005/041960. Isoquinolylalkanol compound (XIIIB) was condensed with trans-2,3-dichlorosuccinic anhydride and triethylamine in acetonitrile solvent to provide a monoester of chlorofumaric acid, which was then condensed with isoquinolylalkanol compound (XIIIC):
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=3)=[N:14][N:15]=2)=[O:10])=[CH:3][CH:2]=1.C1(CCCCCCC(C2OC(C3N=C([C:54]([O:56][CH3:57])=[O:55])C=CC=3)=NN=2)=O)C=CC=CC=1>CO.C(Cl)Cl>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:12][C:13]([C:16]3[N:17]=[C:18]([C:54]([O:56][CH3:57])=[O:55])[CH:19]=[CH:20][CH:21]=3)=[N:14][N:15]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2nnc(C(=O)CCCCCCc3ccccc3)o2)n1
Reactant: O=C(CCc1ccc(-c2ccccc2)cc1)c1nnc(-c2cccc(Br)n2)o1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(-c2nnc(C(=O)CCc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 48 %

Procedure:
The title compound was prepared from 30 (70 mg, 0.16 mmol) by using a procedure similar to that detailed for 8f. Flash chromatography (SiO2, 2.5×15 cm, 0-1% MeOH—CH2Cl2) afforded the title compound (32 mg, 48%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.47 (d, 1H, J=7.8 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.10 (t, 1H, J=7.8 Hz), 7.57 (d, 2H, J=7.2 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.7 Hz), 7.33 (m, 3H), 4.06 (s, 3H), 3.61 (t, 2H, J=7.5 Hz), 3.19 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 150 MHz) δ 186.1, 164.9, 164.6, 161.5, 149.3, 142.9, 141.0, 139.7, 138.9, 138.8, 129.0, 128.9, 127.9, 127.5, 127.3, 127.2, 127.1, 53.4, 41.8, 29.1; HRMS-ESI-TOF m/z 414.1451 ([M+H]+, C24H19N3O4 requires 414.1448).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl.O>CO>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1coc2c(OC)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc2c(CC(=O)O)coc12
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 90.6 %

Procedure:
Methyl (7-methoxy-benzofuran-3-yl)acetate (1.12 g) was dissolved in methanol (20 ml). To this solution, 2N aqueous sodium hydroxide solution (5 ml) was added and the resulting solution was stirred at room temperature for 13.5 hours. To this solution, 1N hydrochloric acid (12 ml) was added and the reaction solution was poured into water layer (200 ml), followed by extraction twice with ethyl acetate (50 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was removed under reduced pressure. The residue was recrystallized from hexane/chloroform to obtain the desired compound (0.95 g, yield: 91%).
Reaction SMILES: [Na:1].N1C(N)=C2C(N(C3(OC[C@H](OCP(O)(O)=O)[C@H]3O)O)C=N2)=NC=1.[N:25]1([C:34]2([O:52][CH2:51][C@H:38]([O:39][CH2:40][P:41]([O:47]C(C)C)([O:43]C(C)C)=[O:42])[C@H:36]2[OH:37])[OH:35])[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>>[Na:1].[N:25]1([C:34]2([O:52][CH2:51][C@H:38]([O:39][CH2:40][P:41]([OH:43])([OH:47])=[O:42])[C@H:36]2[OH:37])[OH:35])[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: Cc1cn(C2(O)OC[C@H](OCP(=O)(OC(C)C)OC(C)C)[C@H]2O)c(=O)[nH]c1=O
Agent: Nc1ncnc2c1ncn2C1(O)OC[C@H](OCP(=O)(O)O)[C@H]1O
Agent: [Na]
Product: Cc1cn(C2(O)OC[C@H](OCP(=O)(O)O)[C@H]2O)c(=O)[nH]c1=O
Yield: 42 %

Procedure:
This compound was prepared as described for 3a, using 16 (220 mg, 0.58 mmol) as starting material. Compound 3b (90 mg, 0.24 mmol) was obtained as a colorless solid in 42% yield, which was characterized as follows:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31](CO)[CH:30]=[C:29]2[O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[CH:41][N:40]=1>O1CCCC1.O>[Br:25][C:26]1[CH:27]=[C:28]2[C:33]([CH:32]=[C:31]([CH2:20][Cl:24])[CH:30]=[C:29]2[O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH3:49])(=[O:46])=[O:47])=[CH:41][N:40]=2)=[CH:34][CH:35]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CO)cc3ccc(Br)cc23)nc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CCl)cc3ccc(Br)cc23)nc1
Temperature: 25 °C
Yield: 76 %

Procedure:
After a solution of triphenylphosphine (330 mg, 1.26 mmol) and carbon tetrachloride (2 mL) in anhydrous tetrahydrofuran (6 mL) was stirred at room temperature for 10 minutes under a nitrogen atmosphere, [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-methanol (265 mg, 0.63 mmol) was introduced as a solid. The resulting mixture was heated at reflux for 4 hours, cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in petroleum ether) to afford 2-(7-bromo-3-chloromethyl-naphthalen-1-yloxy)-5-ethanesulfonyl-pyridine (210 mg, 76%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[N:12][CH:11]=[C:10]([CH:9]=2)[C:20]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: COc1cc(CN)on1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-82-5) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials, LC-MS (UV peak area/ESI) 100%, 442.079 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3Cl)=[CH:8][CH:7]=1)C.[Li+].[OH-].C1COCC1.Cl>CO.[Pd]>[N:16]1[CH:17]=[C:18]2[C:13]([N:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:22])=[O:3])=[CH:11][CH:10]=3)[CH:20]=[N:19]2)=[N:14][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(-n2cnc3c(Cl)ncnc32)cc1
Agent: [Pd]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-n2cnc3cncnc32)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of [4-(6-chloro-purin-9-yl)phenyl]-acetic acid ethyl ester (182 mg, 0.60 mmol) and Pd/C (10%) in MeOH containing 5% ammonia (15 mL) is stirred for 22 h at rt and under hydrogen (2 bar). The reaction mixture is filtered through a pad of celite and concentrated. The residue is purified by silica gel column chromatography (CH2Cl2/MeOH, 95:5), followed by trituration in Et2O to afford a mixture of (4-purin-9-yl-phenyl)-acetic acid methyl and ethyl ester. This mixture is treated with a 2 N aqueous solution of LiOH (0.5 mL), and THF (1 mL) for 3 h at 50° C. The reaction mixture is allowed to cool to rt and then acidified by addition of 0.5 N HCl aqueous solution. The resulting precipitate is collected by vacuum filtration to provide the title compound as a white solid: ES-MS: 255.1 [M+H]+; tR=1.93 min (System 1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:18][S:19]([O:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cn(-c2cccnc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CS(=O)(=O)OCc1cn(-c2cccnc2)c2ccccc12
Temperature: 0 °C

Procedure:
A solution of 3.3 g of 3-hydroxymethyl-N-(3-pyridyl)indole in 25 ml of pyridine is cooled to +5° and 1.36 ml of methanesulfonyl chloride is added dropwise. After 3 hours the reaction is diluted with 75 ml of ice water and 1.5 g of sodium bicarbonate is added. Extraction with methylene chloride (3×25 ml) and drying of the extracts with sodium sulfate yields 3-(methanesulfonyloxymethyl)-N-(3-pyridyl)indole which is used directly in the next step.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1.C[O:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20]2)=O.O>O1CCCC1.C(NC(C)C)(C)C>[CH2:22]1[C:23]2[C:19](=[CH:18][C:17]([C:15](=[O:14])[CH2:12][C:8]3[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc2c(c1)CCC2
Reactant: Cc1cccnc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1cccnc1)c1ccc2c(c1)CCC2
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
In 80 ml of anhydrous tetrahydrofuran was dissolved 8.86 ml of diisopropylamine. The solution was cooled to -10°, to which was added dropwise 39.5 ml of a hexanoic solution of n-butyl lithium (1.6M). Then, the mixture was stirred for 30 minutes at the same temperature, followed by dropwise addition of 5.34 g of β-picoline. The mixture was stirred for 30 minutes, to which was added dropwise 5 g of 5-methoxycarbonyl indane dissolved in 10 ml of anhydrous tetrohydrofuran. Then, the mixture was stirred for one hour at room temperature, followed by addition of about 25 ml of water. The organic solvent was exaporated off under reduced pressure. The concentrated solution was subjected to extraction with ethylacetate. The extract solution was washed with water, dried on magnesium sulfate and concentrated. The concentrate was crystallized from ethylacetate-isopropylether to give 5.6 g (yield 82%) of 1-(5-indanyl)-2-(3-pyridyl)-ethanone, m.p. 55°-56° C.
Reaction SMILES: [NH:1]1[C:14]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[O:4][CH2:3][CH2:2]1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([Br:27])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20].C(N(CC)CC)C.Cl>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([C:19]([N:1]2[C:14]3[CH:13]=[N:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[O:4][CH2:3][CH2:2]2)=[O:20])[CH:22]=[C:23]([Br:27])[C:24]=1[O:25][CH3:26]
Reactant: c1ccc2c3c(cnc2c1)NCCO3
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3c2cnc2ccccc32)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
In a 10 ml flask, 2,3-dihydro-1H-4-oxa-1,9-diaza-phenanthrene (50 mg, 0.269 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (88 mg, 0.269 mmol) were dissolved in dichloromethane. Triethylamine (0.51 ml, 3.7 mmol) was added thereto and then stirred at room temperature for 3 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=20:1. The fractions containing the product were collected and evaporated to obtain the target compound as yellow solid (110 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1cccs1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]([C:16]([CH2:18]Cl)=[O:17])([CH3:15])[CH3:14]>CC(C)=O>[CH3:12][C:13]([CH3:15])([CH3:14])[C:16](=[O:17])[CH2:18][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)C(=O)CCl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Cn1ccnc1
Temperature: 25 °C
Yield: 89 %

Procedure:
136.2 g (2 moles) of imidazole were added in portions, at room temperature, to 276.4 g (2 moles) of ground potassium carbonate and 269.2 g (2 moles) of α-chloropinacolin in 500 ml of acetone, whereupon the internal temperature rose to the boiling point. The mixture was stirred under reflux for 5 hours and then cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. The oily residue was distilled. 296 g (89% of theory) of 3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one of melting point ~20° C. were obtained. ##STR45##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:14]2[N:15]=[N:16][NH:17][N:18]=2)[CH2:10][C@H:9]1[CH2:34][CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:38](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([C:30]([F:32])([F:33])[F:31])[CH:21]=2)[C:14]2[N:15]=[N:16][N:17]([CH3:38])[N:18]=2)[CH2:10][C@H:9]1[CH2:34][CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)CN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CN1C(=O)OC(C)(C)C
Yield: 86.1 %

Procedure:
A solution of the crude (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (52 mg, 0.10 mmol), methyl iodide (90 mg, 0.51 mmol) and potassium carbonate (28 mg, 0.20 mmol) in DMF (1.3 mL) is stirred at 50° C. for 2 hours. The reaction mixture is quenched with saturated ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (45 mg, 44% overall yield in 4 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[O:5][CH2:6][C@@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8]>[Pd].C(O)C>[NH2:20][C:19]1[CH:18]=[CH:17][C:4]([O:5][CH2:6][C@@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH3:8])=[CH:3][C:2]=1[F:1]
Reactant: C[C@@H](COc1ccc([N+](=O)[O-])c(F)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](COc1ccc(N)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Under a hydrogen atmosphere, a mixture of tert-butyl [(1S)-2-(3-fluoro-4-nitrophenoxy)-1-methylethyl]carbamate (10.2 g), 10% palladium/carbon (containing water (50%), 500 mg) and ethanol (150 mL) was stirred at room temperature for 1 hr. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure to give the title compound as a brown solid (8.64 g).
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)=[CH:8][CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:31]([CH:33]([CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1)[C:34](OC)=O)=[O:32].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:46][O:45][C:42]1[N:41]=[CH:40][C:39]([CH2:38][C:33]2[C:31](=[O:32])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:34]=2)=[CH:44][N:43]=1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)nc2=O)cn1
Temperature: 80 °C

Procedure:
To the solution of 4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenethyl carbamimidate, Trifluoroacetate (600 mg, 1.369 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (246 mg, 1.095 mmol) in 1,4-dioxane (6 mL) was added K2CO3 (757 mg, 5.48 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (2 mg, 0.293 yield). LCMS: rt=3.09 min, [M+H+]=500
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)=O.O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCC(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)CCCCI
Yield: 82.9 %

Procedure:
Sodium iodide (168 g, 1.12 mol) was added to a solution of 1-methanesulfonyloxy-5,5,6,6,6-pentafluorohexane (101 g, 373.77 mmol) in acetone (2000 ml), followed by heating under reflux for 12 hours. Water was added to the reaction mixture, which was then extracted twice with ether. The combined organic layers were washed with 1% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: pentane) to give 1-iodo-5,5,6,6,6-pentafluorohexane (93.6 g, Yield 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=1)=[O:20]
Reactant: COc1ccccc1NS(C)(=O)=O
Reactant: O=C(Cl)CCCCCl
Product: COc1ccc(C(=O)CCCCCl)cc1NS(C)(=O)=O

Procedure:
Using N-(2-methoxyphenyl)methanesulfonamide (10.0 g) and 5-chlorovaleryl chloride (7.06 ml) according to the same method as that of Reference Example 1, the title compound (9.15 g) was obtained as colorless crystals.