Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(F)cc1)OCc1ccccc1
Reaction time: 3 h
Yield: 43.7 %

Procedure:
Benzylchloroformate (12.2 g, 72 mmol) was added dropwise to a stirred solution, at 0° C., of 4-fluorophenylethyl amine (9.42 g, 72 mmol) in 50 mL of DMF. The mixture was stirred for an additional 3 hours at the same temperature. The reaction was quenched with water and extracted with 3×100 mL of ethyl acetate. The combined ethyl acetate extracts were washed with 2×100 mL of 5% HCl, water and dried over Na2SO4. Evaporation of the solvent resulted in a yellowish solid which was purified by recrystallization from ethyl acetate-hexane to furnish 8.6 g (46% yield) of N-Benzyloxycarbonyl-2-(parafluorophenyl)ethylamine. mp 51°-52° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:30])[C:10]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[CH2:23]([N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:10]1[N:9]([CH3:30])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnn(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)cnn2C)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 0.799 g (1.862 mmol) of the product of Example 7 in 20 mL of methanol/THF (1:1) was added 9.3 mL of 1N sodium hydroxide solution and the resulting mixture was heated to reflux for 18 h. The reaction was then cooled to room temperature and the organics were removed in vacuo. The resulting mixture was acidified with 10% HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 0.697 g (93%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec: 402 (M+H).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[O-:8][OH:9].[C:10]1([CH:16]([CH3:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:6][C:5]([O:8][O:9][C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:18])[CH3:17])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(C)c1ccccc1
Reactant: CC(=O)C=C(C)C
Reactant: [O-]O
Product: CC(=O)CC(C)(C)OOC(C)(C)c1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 3.4 g. (0.035 mole) of mesityl oxide and 1.0 g. of Amberlyst 15® sulfonic acid type ion-exchange resin was stirred at 25°-30° C., while 7.6 g. (0.050 mole) of 80% cumene hydroperoxide was added slowly. After stirring for 5 hours, the ion-exchange resin was separated by filtration, 25 ml. of pentane added and the filtrate washed with cold aqueous sodium bisulfite solution, sodium hydroxide solution and water. The pentane solution of the product was dried over anhydrous magnesium sulfate and the pentane removed under reduced pressure. The product recovered weighed 5.9 g. and was identified by its infrared spectrum.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16](O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(OC(=O)C)(=[O:22])C.C(OCC)(=O)C>C(Cl)Cl.[O-2].[Cr+6].[O-2].[O-2]>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chromium (vi) oxide (800 mg, 8.0 mmol) was added to pyridine (1.6 mL) in CH2Cl2 (10 mL) and the resulting solution was stirred for 15 min at room temperature. A solution of tert.butyl-3-hydroxy-1-pyrrolidinecarboxylate (374.5 mg, 2.0 mmol) in CH2Cl2 (5 mL) was added, immediately followed by acetic anhydride and the reaction mixture kept at room temperature for 15 min. After addition of ethyl acetate, decanted and filtered through a short column of silica gel. The filtrate was concentrated to give the subtitled product (193 mg) and was used directly in the next step.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([NH:23][NH2:24])=[O:22])[N:13]=2)[CH:9]=[N:8]1.C(Cl)Cl.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>CCOC(C)=O>[C:37]([NH:24][NH:23][C:21]([C:14]1[N:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:25])[CH3:1])[CH:11]=2)[N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[CH:15]=1)=[O:22])(=[O:39])[CH3:38]
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(C(=O)NN)cc3nccn23)cn1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NNC(=O)c1cc2nccn2c(-c2cnn(COCC[Si](C)(C)C)c2)n1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
In a 20 mL flask, 5-(1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carbohydrazide (45.1 mg, 0.121 mmol) was dissolved in DCM (604 μL, 0.121 mmol). After cooling to 0° C., triethylamine (20.2 μL, 0.145 mmol) and acetyl chloride (9.45 μL, 0.133 mmol) were added. The reaction mixture was allowed to warm to ambient temperature for 15 hours. This was then diluted in EtOAc and washed with water and brine. The organic layer was then dried with MgSO4, filtered and concentrated down to afford N′-acetyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carbohydrazide (40.9 mg, 81.5% yield) as a light yellow solid. MS (apci) m/z=416.2 (M+H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11](C(O)=O)[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])[CH2:9]1)=[O:7])(C)(C)C.C1C=CC(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+].[C:51]1([CH3:57])[CH:56]=CC=C[CH:52]=1>O>[C:51]([CH:9]1[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])[C@H:11]([NH2:39])[CH2:12][CH2:13][N:8]1[C:6]([OH:5])=[O:7])([CH3:57])([CH3:56])[CH3:52]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Reactant: Cc1cc(F)ccc1[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1[C@H]1C(C(C)(C)C)N(C(=O)O)CC[C@H]1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of (3R*,4R*)-1-(tert-butoxycarbonyl)-3-(4-fluoro-2-methylphenyl)piperidine-4-carboxylic acid (4.33 g) synthesized by a known method (WO2006/004195) in toluene (24 mL) were added DPPA (5.30 g) and triethylamine (2.7 mL) at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled, 8N aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 30→70% ethyl acetate/hexane) to give tert-butyl (3R*,4R*)-4-amino-3-(4-fluoro-2-methylphenyl)piperidine-1-carboxylic acid (3.79 g, 96%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:10]=1[C:11](O)=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:9]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:11](=[O:12])[C:10]=2[CH:14]=1
Reactant: Nc1ccccc1Sc1ccc(F)cc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1Nc2ccccc2Sc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-(2-aminophenylthio)-5-fluorobenzoic acid (64.57 mmol, 17.51 g) in 500 mL xylenes was treated with p-toluenesulfonic acid monohydrate (64.57 mmol, 12.2 g) and heated. Additional 200 mL xylene was added and heating was continued with azeotropic removal of water for 16 h. The resulting pink reaction mixture was cooled to the room temperature and added to 300 mL water. After stirring for 15 min the solid removed by filtration, washed with 3×100 mL water and dried in air for 4 h, and then under high vacuum for 20 h to obtain 2-fluorodibenzo[b,f][1,4]thiazepin-11(10H)-one as a off white solid (11.6 g, 73%); MS (M+1) 246; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.16 (t, 1H) 7.24 (d, J=7.2 Hz, 1H) 7.29-7.42 (m, 2H) 7.47 (dd, J=9.3, 2.9 Hz, 1H) 7.52-7.71 (m, 2H) 10.47-11.20 (m, 1H), MS 081119 M+1 246 (0.72).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2[nH]c3ccccc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCc2c(c3ccccc3n2S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3 g of 1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester in methylene chloride (50 mL) is treated with 0.982 g of sodium hydroxide and stirred and room temperature overnight. Benzenesulfonylchloride (6.30 mL) is added to the reaction and stirred at room temperature overnight. The reaction mixture is diluted with water (250 mL) and extracted with methylene chloride. The organics are combined, washed with water then a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 5-benzenesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester as a yellow powder. MS (m/z): 385 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([NH:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[N:8][C:6]=2[N:7]=1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(NCCN3CCOCC3)nc2n1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 2-morpholinoethanamine via General Procedure C to give crude 5-chloro-7-morpholino-N-(2-morpholinoethyl)thiazolo[4,5-d]pyrimidin-2-amine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure C again to give 136 after purification by reverse HPLC. MS (Q1) 444 (M+)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:21][C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: Oc1ccc(C2=CCC(c3ccc(O)cc3)CC2)cc1
Reactant: Oc1ccc(C2CCC(c3ccc(O)cc3)CC2)cc1
Product: Oc1ccc([C@H]2CC[C@@H](c3ccc(O)cc3)CC2)cc1
Product: Oc1ccc([C@H]2CC[C@H](c3ccc(O)cc3)CC2)cc1

Procedure:
More particularly, 1,4-bis(4-hydroxyphenyl)-1-cyclohexene is hydrogenated, and the resulting reaction mixture which contains 4-(4′-(4″-hydroxyphenyl)cyclohexyl)-1-hydroxybenzene is subjected to conventional purification methods to provide a purified product, and the product is then dissolved in an organic solvent which is suitably used in column separation processes, such as methanol, acetonitrile or tetrahydrofuran, or alternatively, the reaction mixture obtained is subjected to solvent replacement by an organic solvent which is suitably used in column separation processes, such as methanol, acetonitrile or tetrahydrofuran. Then, the resulting solution of the product or the solution of the reaction mixture in such an organic solvent as mentioned above is subjected to cis-trans separation operations by a suitable means such as preparative high performance liquid chromatography making use of difference of retention time so that the cis- and trans-isomer, that is, 4-(trans-4′-(4″-hydroxyphenyl)cyclohexyl)-1-hydroxybenzene and 4-(cis-4′-(4″-hydroxyphenyl)cyclohexyl) 1-hydroxybenzene, are separately obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:19][NH:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].CC1(C)C(C)(C)OB([C:40]2[CH:48]=[CH:47][CH:46]=[C:45]3[C:41]=2[CH:42]=[N:43][NH:44]3)O1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:44]1[C:45]2[C:41](=[C:40]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([C:27]5[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=5)[C:21]([NH:20][CH3:19])=[O:22])=[C:8]([CH3:12])[C:6]=4[N:7]=3)[CH:48]=[CH:47][CH:46]=2)[CH:42]=[N:43]1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)c1cccc(-c2sc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3c2C)c1
Temperature: 150 °C

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine from Example 12 (0.1 g, 0.3 mmol), 3-(N-Methylaminocarbonyl)benzeneboronic acid (50 mg, 0.3 mmol), and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13 μmol) in 1 M aqueous Na2CO3 (0.5 mL) and acetonitrile (0.5 mL) were heated to 100° C. in a sealed microwave reactor for 10 min. Upon completion, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (122 mg, 0.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13 mmol), 1 M aqueous Na2CO3 (1 mL), and acetonitrile (1 mL) were added into the same pot. The reaction mixture was heated to 150° C. in a sealed microwave reactor for 20 min. The mixture was extracted with EtOAc and CF2Cl2. The combined organics were concentrated to yield 358 after reverse phase HPLC purification (2 mg). MS (Q1) 485 (M)+
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]1[CH2:24][CH2:23][S:22][CH2:21][C:20]1=[O:25]>C(O)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:20](=[O:25])[CH2:21][S:22][CH2:23][CH2:24][OH:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: O=C1CSCCO1
Solvent: CCO
Product: O=C(CSCCO)NCCCOc1cc(CN2CCCCC2)ccn1
Yield: 87.5 %

Procedure:
A mixture of 0.38 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and 0.18 g of 1,4-oxathian-2-one was added to 10 ml of ethanol, and the resulting mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The concentrate was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.49 g (yield 88%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1.[C:14]([O-:17])([O-])=O.[Na+].[Na+].[CH2:20]([Cl:22])Cl>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:22][C:20]1[CH:11]=[CH:12][C:2]([O:17][CH3:14])=[CH:3][C:4]=1[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]=[C:7]([NH2:10])[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: ClCCl
Reactant: Cc1cc(Br)cc2nnc(N)nc12
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Temperature: 100 °C

Procedure:
7-bromo-5-methyl-benzo[1,2,4]triazin-3-ylamine (33.47 mmol, 1.0 equiv), 1-chloro-4-methoxy-2-boronic acid (50.21 mmol, 1.5 equiv), Pd(PPH3)4 (3.347 mmol, 0.1 equiv), and Na2CO3 (133.9 mmol, 4.0 equiv) were dissolved in DME/EtOH/water 6:1:1 and refluxed at 100° C. under an argon blanket for 4 h. The reaction was cooled to room temperature, diluted with 100 mL DCM and filtered. The precipitate that was recovered was suspended in water, filtered and rinsed with ether. The precipitate afforded 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine, as a green solid (8.37 g, 84% yield). Rf=0.85 (9:1 DCM/MeOH). 1H NMR (DMSO-d6): δ 3.35 (s, 6H), 7.01 (dd, J=8.8 Hz, J=3.0, 1H), 7.09 (d, J=3.0 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.75 (bm, 2H). MS (ES+) m/z=303. LC retention time 3.03 min.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.N1CCCC(C(OCC)=O)C1.[S:31]1C=CC=C1C(Cl)=O>>[S:31]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:8]
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: O=C(Cl)c1cccs1
Agent: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(=O)c2cccs2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl nipecotate (202.9 mg; 1.29 mmol) and commercially available 2-thiophenecarbonyl chloride (138 μl; 1.29 mmol). The crude product was distilled at 225° C./0.1 torr, giving ethyl (2-thiophenecarbonyl)-3-piperidinecarboxylate (249.8 mg) as a yellow oil. MS m/z (positive ion) 290 (M+Na+; 40), 268 (MH+; 100).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]NC(=O)C)[C:8]=32)=[N:3]1.[CH3:20][CH:21]([NH:29]CCC#N)CC1C=CC=CC=1.Cl.CCCCCC.C([OH:43])C>>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:20][C:21]([NH2:29])=[O:43])[C:8]=32)=[N:3]1
Reactant: CCO
Reactant: CC(Cc1ccccc1)NCCC#N
Reactant: CC(=O)NCCC1CCc2ccc3nn(C)cc3c21
Agent: Cl
Solvent: CCCCCC
Product: Cn1cc2c3c(ccc2n1)CC[C@@H]3CCCC(N)=O

Procedure:
N-[2-(2-Methyl-2,6,7,8-tetrahydrocyclopenta[e]indazol-8-yl)ethyl]acetamide (about 70 mg) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 80 mL/min, column temperature: room temperature, sample concentration: 1.0 mg/mL (hexane/ethanol=90/10), injection amount: about 35 mg). A fraction solution containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was further added, and the mixture was concentrated to dryness again to give the title compound (37 mg, 99% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0 mL/min, column temperature: room temperature, sample concentration: 1 mg/mL (hexane/ethanol=90/10), injection volume: 10 μL).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:19]1[CH:20]=[C:21]([Cl:30])[C:22]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[N:23][CH:24]=1>>[Cl:30][C:21]1[CH:20]=[C:19]([C:2]2[O:1][C:5]3[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:24]=[N:23][C:22]=1[O:25][CH2:26][CH:27]1[CH2:28][CH2:29]1
Reactant: CC(=O)N[C@@H](C)COc1ccc2ncoc2c1
Reactant: Clc1cc(Br)cnc1OCC1CC1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cnc(OCC4CC4)c(Cl)c3)oc2c1

Procedure:
Using N-((2S)-1-(1,3-benzoxazol-6-yloxy)propan-2-yl)acetamide and 5-bromo-3-chloro-2-(cyclopropylmethoxy)pyridine, and in the same manner as in Step B of Example 22, the title compound was obtained.
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH2:17].[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:28]2=[O:39])[S:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38])[C:28]2=[O:39])[S:22][C:23]=1[C:24]([NH:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)=[O:25]
Reactant: NCc1ccccn1
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1ccccn1
Yield: 28 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-2-ylmethanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 28% yield: 1H NMR (300 MHz, CDCl3) δ 8.56-8.54 (m, 1H), 7.70-7.64 (m, 1H), 7.30-7.19 (m, 2H), 7.13-7.10 (m, 1H), 4.69 (d, J=4.6 Hz, 2H), 4.17-4.11 (m, 2H), 3.63-3.58 (m, 2H), 2.65 (s, 3H), 2.24-2.08 (m, 2H), 1.92-1.75 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 162.5, 157.5, 155.8, 155.6, 152.3, 148.9, 136.7, 122.4, 121.9, 118.2, 44.6, 42.9, 42.3, 42.0, 31.8, 31.4, 30.9, 30.6, 20.2, 20.1, 17.3; MS (ES+) m/z 427.9 (M+1).