Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 2-hydroxy-4-iodobenzoate (22.8 g), benzyl bromide (10.3 ml) and K2CO3 (22.67 g) in DMF (200 ml) was stirred at rt for 72 h. The mixture was partitioned between diethyl ether and water, the organics separated washed with water, dried and evaporated under reduced pressure to give a white solid, 29.5 g.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[CH2:17][C@H:18]1[CH2:20][O:19]1>CN(C)C=O>[O:19]1[CH2:20][C@@H:18]1[CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: ClC[C@H]1CO1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2C[C@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a stirred solution of carbazole (2.0 g, 12 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added 85% aqueous potassium hydroxide (0.95 g, 14.4 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was cooled in an ice bath and (R)-(−)-2-(chloromethyl)oxirane (2.77 g, 29.9 mmol) was added. The mixture was stirred overnight at room temperature, and then partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by recrystallization from ethyl acetate/hexanes to afford the desired product as white crystals (0.8 g, 30%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 7.55-7.40 (m, 4H), 7.32-7.22 (m, 2H), 4.66 (dd, 1H, J=15.9, 3.3 Hz), 4.43 (dd, 1H, J=15.9, 4.8 Hz), 3.38 (m, 1H), 2.83 (t, 1H, J=4.5 Hz), 2.60 (dd, 1H, J=4.8, 2.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:18].[Na+]>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: COC(=O)C=CC=CCSc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C=CC=CCS(=O)c1ccccc1
Temperature: 20 °C
Yield: 81 %

Procedure:
To a solution of 6-phenylsulfanyl-hexa-2,4-dienoic acid methyl ester (0.336 g, 1.43 mmol) in methanol (17 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (0.37 g, 1.72 mmol) in distilled water (6 mL). The mixture was allowed to warm to 20° C. and then heated at reflux for 5 hours. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (10 mL) and then brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (1:2 to 1:1 to 2:1 ethyl acetate:60-80 ° C. petroleum ether). The resulting powder was recrystallised from diethyl ether to give the title compound (0.29 g, 81%) as a white solid, mp 82-84° C.
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[N:7][C:6]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[N:14][C:5]1=2.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Si:19]([O:18][CH2:17][CH:2]([OH:1])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[N:7][C:6]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[N:14][C:5]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COc1ccc2ncc(=O)n(CC(O)CO)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.4 %

Procedure:
In dichloromethane (30 ml) was dissolved 4-(2,3-dihydroxypropyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.34 g, 5.32 mmol). To the solution were added tert-butyldimethylsilyl chloride (882 mg, 5.85 mmol), triethylamine (0.96 ml, 6.92 mmol) and 4-dimethylamino pyridine (130 mg, 1.06 mmol) under cooling on ice and the reaction mixture was stirred for 15 hours while the temperature was raised to room temperature. Saturated sodium bicarbonate water was added to the reaction solution, which was extracted with dichloromethane and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 1.35 g (70%) of the title compound in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])([C:5]([F:8])([F:7])[F:6])[O-:4].[Li+].[S:16](F)([F:19])([F:18])[F:17]>C(OCCCC)CCC>[F:1][C:2]([F:13])([F:14])[C:3]([C:5]([F:8])([F:7])[F:6])([C:9]([F:11])([F:12])[F:10])[O:4][S:16]([F:19])([F:18])[F:17]
Reactant: FS(F)(F)F
Reactant: [O-]C(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: CCCCOCCCC
Product: FC(F)(F)C(OS(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: -70 °C
Yield: 20.9 %

Procedure:
A solution of 10.5 g (0.043 mol) of lithium 2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxide in 60 ml of dibutyl ether was added dropwise to a solution of 8 ml (measured at -78° C., 0.15 mol) of sulfur tetrafluoride in 50 ml of dibutyl ether cooled to -70° C. The reaction mixture was warmed to 25° C., and the volatiles were distilled out at reduced pressure and condensed in a cold trap at -78° C. The condensate was fractionated to give (A) 2.91 g of 2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxysulfur trifluoride as a colorless liquid: bp 56° to 60°; 19F NMR (CCl3F) δ -71.4 ppm (q, J=3.0 Hz, 9F) and 44.0 ppm (broad, 3F) and (B) 3.60 g of bis[2,2,2-trifluoro-1,1-(trifluoromethy)ethoxy]sulfur difluoride as a colorless liquid: bp 35° to 37° C. (20 mm); 19F NMR (CCl3F) δ -71.7 ppm (t, J=1.5 Hz), 18F) and +32.1 ppm (broad, 2F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][N:33]([CH3:44])[CH2:34][CH2:35][N:36]([C@H:37]1[CH2:38][CH2:39][C@H:40]([CH3:43])[CH2:41][CH2:42]1)[C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 2.7 g of 3,4-dimethoxycinnamic acid, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3.0 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.53 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,4-dimethoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[S:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=1>>[C:15]1([C:12]2[N:11]=[C:10]([O:1][CH2:2][C:3]3([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]3)[S:14][N:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCC1(CO)CCC1
Reactant: Clc1nc(-c2ccccc2)ns1
Product: OCC1(COc2nc(-c3ccccc3)ns2)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a from [1-(hydroxymethyl)cyclobutyl]methanol and 5-chloro-3-phenyl-1,2,4-thiadiazole. 1H NMR (300 MHz, CDCl3) δ 8.10 (m, 2H), 7.39 (m, 3H), 4.63 (s, 2H), 3.62 (d, J=6 Hz, 2H), 2.71 (t, J=6 Hz, 1H), 1.88-1.97 (m, 6H). GC-MS m/z 277 (M+H).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:13]([O:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCCCOC[C@H](COCc1ccccc1)OCCCCCCCCCCCCCCCCCCCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCCCCCC
Yield: 72.2 %

Procedure:
3-O-benzyl-1,2-di-O-eicosyl-Sn-glycerol (1.47 g, 1.98 mmol) and 10% palladium-charcoal (200 mg) were stirred in ethyl acetate (30 ml) under the hydrogen atmosphere at room temperature for 18 h. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to obtain the title compound (934 mg, 72%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1N
Yield: 100.2 %

Procedure:
A solution of 3-amino-4-methylbenzoic acid (1.36 g, 9.0 mmol), (4-(piperidin-4-yl)benzonitrile HCl salt (compound 1.5, 2.0 g, 9.0 mmol), EDCI (1.89 g, 9.9 mmol), HOBT (1.66 g, 9.9 mmol, with 20% H2O) and DIEA (3.13 ml, 18.0 mmol) in DMF (50 ml) was stirred at room temperature overnight. The reaction mixture was poured into cold water (300 ml) and off white solids precipitated. The precipitate was filtered, washed with water and dried under reduced pressure in an oven to yield 2.88 g (100%) of the title compound. m/z (ES+) 320 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:35])[NH:20][C:21]1([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.CCOC(C)=O>S(Cl)(Cl)=O.C(Cl)Cl.CCCCCC>[C:14]([O:18][C:19](=[O:35])[NH:20][C:21]1([CH2:26][N:27]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)[C:11]([C@@H:9]2[CH2:10][C@H:8]2[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[O:13])[CH2:22][CH2:23][CH2:24][CH2:25]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)[C@@H]1C[C@H]1c1cccc(F)n1
Reactant: CC(C)(C)OC(=O)NC1(CNc2ccc(Br)cc2)CCCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC1(CN(C(=O)[C@@H]2C[C@H]2c2cccc(F)n2)c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A mixture of trans-2-(6-fluoro-pyridin-2yl)-cyclopropanecarboxylic acid (˜0.9 mmol) in thionyl chloride (2 mL) was heated at reflux for overnight. The mixture was concentrated and dried under high vacuum for 2 h. Then the residue was dissolved in DCM (4 mL) and added dropwise to a solution of {1-[(4-Bromo-phenylamino)-methyl]-cyclopentyl}-carbamic acid tert-butyl ester (370 mg, 1 mmol) and triethyl amine (280 uL) in DCM (4 mL). The resulting mixture was stirred at rt for over night. The reaction mixture was subjected to flash column directly (20% EtOAc in hexane) to give the desired product as a white solid (348 mg, ˜70%). MS (MH+ 532 and 534).
Reaction SMILES: [Cl:1][C:2]1[C:3](NN)=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8]>CC(O)C.C(Cl)(Cl)Cl.C(O)C.[Ag]=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)c(NN)nc(=O)n1Cc1cccs1
Agent: O=[Ag]
Solvent: CC(C)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cnc(=O)n1Cc1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Silver oxide (238 mg) was added to a solution of 5-chloro-4-hydrazino-6-methyl-1-(2-thienylmethyl)pyrimidin-2-one (128 mg) in propan-2-ol (20 ml). The mixture was stirred at ambient temperature for 24 hours, when evaporation of solvent gave a gum. This was subjected to p.l.c. on silica, developing in chloroform-ethanol (25:1, two runs). The major band was eluted with ethyl acetate giving a gum (23 mg) containing the title pyrimidinone p.m.r. spectrum in CDCl3, signals relative to SiMe4 in p.p.m.: 2.6 (3H, s) 6-CH3 ; 5.4 (2H,s) 1-CH2 -.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(OC(=O)[NH:41][CH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([N:51]=[C:52]([NH:54][CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)[CH3:53])[CH:49]=2)[CH2:44][CH2:43]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:63][C:60]1[CH:59]=[CH:58][C:57]([CH2:56][CH2:55][NH:54][C:52](=[N:51][C:48]2[CH:49]=[C:50]3[C:45]([CH2:44][CH2:43][C@H:42]3[NH:41][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:19])[F:18])=[CH:14][CH:13]=3)=[O:17])=[CH:46][CH:47]=2)[CH3:53])=[CH:62][CH:61]=1
Reactant: CC(=Nc1ccc2c(c1)C(NC(=O)OC(C)(C)C)CC2)NCCc1ccc(F)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=Nc1ccc2c(c1)[C@H](NC(=O)c1ccc(-c3ccccc3C(F)(F)F)cc1)CC2)NCCc1ccc(F)cc1
Yield: 46.8 %

Procedure:
Stir a mixture of 2′-trifluoromethylbiphenyl-4-carboxylic acid (100 mg, 0.376 mmol), N-hydroxysuccinimmide (43 mg, 0.376 mmol) and DCC (77 mg, 0.376 mmol) in 15 mL of methylene chloride at rt for 2 h. Combine (6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)indan-1-yl)carbamic acid tert-butyl ester (129 mg. 0.313 mmol) with TFA (2 mL) at 0° C. and stir for 2 hr. Evaporate TFA under reduced pressure. Dissolve the residue in methylene chloride and evaporate to dryness; repeat this three times. Add 5 mL of methylene chloride and 1 mL of triethylamine. Add this resulting solution to the above mixture and stir at rt for 12 h. Pour the mixture into methylene chloride, wash with water, dry with Na2SO4, and concentrate. Purify the residue by column chromatography (silica gel, 3% MeOH in CH2Cl2) to give 82 mg of the title compound as a white solid (47% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17]([CH3:19])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.SC[CH2:22][C:23]([OH:25])=[O:24].C1CCN2C(=NCCC2)CC1>C1COCC1.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:19][CH2:22][C:23]([OH:25])=[O:24])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: O=C(O)CCS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(O)CCSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.42 h
Yield: 80.2 %

Procedure:
To a solution of solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (141 mg, 0.50 mmol) in THF (3 mL) was added 3-mercaptopropionic acid (88 μL, 1.0 mmol) followed by DBU (320 μL, 2.1 mmol). The solution was stirred for 25 min, diluted with 1% NaHCO3, and extracted with ethyl acetate. The aqueous layer was acidified with 3% HCl to afford a white precipitate. The solids were collected by filtration, washed with water and dried to afford 128.8 mg (79% yield) of the titled compound as a white solid. API-MS m/z 322 (MH+), 320 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@@H:18]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[CH:20]([CH2:21][CH2:22][C@@H:23]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:17][C@@H:18]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[CH:20]([CH2:21][CH2:22][C@@H:23]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]1)=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 56 %

Procedure:
By using N-tert-butyloxycarbonyl-L-asparagine (464 mg, 2.00 mmol) and 3α-aminocholestane (777 mg, 2.00 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (670 mg, yield; 56%).
Reaction SMILES: [CH:1]1([C:5]([O-:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13]([N:15]1CC(C(OC)=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:4][C:1]([CH2:2][CH3:3])([C:5]([OH:7])=[O:6])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C([O-])C1CCC1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Product: CCC1(C(=O)O)CN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described for Reference Example 10 substituting cyclobutanecarboxylate with methyl 1-tert-butoxycarbonylazetidine-3-carboxylate. 1H NMR (500 MHz, CD3OD): δ 4.12 (d, 2H), 3.70 (d, 2H), 1.82 (q, 2H), 1.42 (s, 9H), 0.90 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[NH:10][N:9]=[C:8](N)[C:5]2=[N:6][CH:7]=1.CC(O)=O.N([O-])=O.[Na+]>O>[F:1][C:2]1[C:3]([I:12])=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1n[nH]c2c(I)c(F)cnc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cnc2cn[nH]c2c1I
Temperature: 40 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
6-Fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridin-3-amine (250 mg) was combined with water (4 mL) and AcOH (6 mL) was heated to 40° C. until the solution became clear. The reaction mixture was then cooled to 0° C. and a solution of sodium nitrite (137 mg) in water (1 mL) was added dropwise over about 30 minutes. The reaction mixture was then warmed to room temperature, and stirred for 16 hours. The reaction mixture was again cooled to 0° C. and stirred for another 0.5 hour to give a solid which was collected by filtration, and washed with cold water. The solid were suspended in diluted HI (0.25 mL 50% HI diluted with water to 2.75 mL) and dimethoxyethane (6.5 mL) and the reaction mixture was heated to 80° C. for 3 hours, then cooled to room temperature, neutralized with Na2CO3 solution, and then extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give a residue which was purified by silica gel chromatography eluting with petroleum ether-ethyl acetate (5:1) to afford the title compound (120 mg, 50.6% yield) as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 13.77 (s, 1H) 8.50 (s, 1H) 8.40 (s, 1H). MS [M+H] found 264.0.
Reaction SMILES: CN(C)[CH:3]=[N:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:7][N:6]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:31]([O:30][C:28]([C:27]1[N:6]2[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:5]2=[N:4][CH:3]=1)=[O:29])[CH3:32]
Reactant: CN(C)C=Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 120 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
A mixture of the above N,N-dimethyl-N′-[3-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-formamidine (3.61 g, 10.0 mmol) and ethyl bromoacetate (3.32 mL, 30.0 mmol) in DMF (10 mL) was stirred at 120° C. for 4 h. Cooled down to 100° C., added DIPEA (0.5 mL, 3.0 mmol) and stirred at 23° C. for 2 h. Poured into sat. NaHCO3-sol., extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil (5.01 g) which was purified by silica gel column chromatography with heptane/EtOAc 9:1 to 4:1 to give the title compound as a light yellow solid (2.89 g, 72%). MS (ISP) 403 [(M+H)+]; mp 132° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][NH:16]C(=O)OC(C)(C)C.[ClH:24].CO>CO>[ClH:24].[ClH:24].[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][NH2:16]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)OC(C)(C)C)c(F)ccc2n1
Agent: Cl
Solvent: CO
Product: Cn1cc2c([C@@H]3C[C@H]3CN)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {[(1R,2R)-2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}carbamate (343 mg, 1.07 mmol) in methanol (1 mL) was added hydrochloric acid-methanol reagent (manufactured by TCI, 3 mL) solution, and the mixture was stirred at room temperature for 14 hr. The solvent was concentrated under reduced pressure and the obtained crystals were washed with ethyl acetate to give the title compound (246 mg, yield 79%).
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1.[Mg].[CH:14]1([C:17]2[CH:18]=[CH:19][C:20]([CH:25]=[O:26])=[N:21][C:22]=2[O:23][CH3:24])[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[CH:18]=[CH:19][C:20]([CH:25]([C:4]3[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=3)[OH:26])=[N:21][C:22]=2[O:23][CH3:24])[CH2:16][CH2:15]1
Reactant: CCOc1ccc(Br)cc1
Reactant: COc1nc(C=O)ccc1C1CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(C(O)c2ccc(C3CC3)c(OC)n2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A small amount of iodine was added to a suspension of 1-bromo-4-ethoxybenzene (484 μL) and magnesium (82.3 mg) in THF at room temperature in a nitrogen atmosphere, and the mixture was stirred at 50° C. for one hour. The reaction solution was returned to room temperature and a solution of 5-cyclopropyl-6-methoxypyridine-2-carbaldehyde (300 mg) in tetrahydrofuran (1 mL) was added, followed by stirring at 50° C. for one hour. Tetrahydrofuran was concentrated under reduced pressure and a saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was filtered through diatomaceous earth, and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→9:1) to give (5-cyclopropyl-6-methoxypyridin-2-yl)(4-ethoxyphenyl)methanol as a yellow oil (438 mg, 86%).