Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:23]C)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Agent: Cl
Product: COCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 84.2 %

Procedure:
6-Amino-9-benzyl-8-methoxy-2-(2-methoxyethoxy)purine (21 mg, 0.064 mmol) in concentrated hydrochloric acid (20 ml) was stirred at room temperature for 5 hours. The reaction mixture was evaporated in vacuo to dryness and 28% aqueous ammonia was added to the residue. The resulting crystals were filtered and washed with water to give the subject compound (17 mg, yield 84%).
Reaction SMILES: C([O:3][C:4]([C@:6]1([NH:23][C:24](=[O:34])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][C@H:10]([S:12][C:13]2[NH:17][CH:16]=[N:15][N:14]=2)[C@@H:9]2[C@H:7]1[C@H:8]2[C:18]([O:20]CC)=[O:19])=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[C:30]([O:29][C:27]([NH:26][CH2:25][C:24]([NH:23][C@@:6]1([C:4]([OH:5])=[O:3])[CH2:11][C@H:10]([S:12][C:13]2[NH:17][CH:16]=[N:15][N:14]=2)[C@@H:9]2[C@H:7]1[C@H:8]2[C:18]([OH:20])=[O:19])=[O:34])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2Sc1nnc[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@]1(C(=O)O)C[C@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.4 %

Procedure:
Dissolve diethyl(1R,2S,4S,5R,6R)-2-[[-2-(tert-butoxycarbonylamino) acetyl]amino]-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.420 g, 0.84 mmol) in tetrahydrofuran (7 mL) then add 2.5M lithium hydroxide (6.7 mL, 16.88 mmol). Stir the mixture at room temperature for 3.5 hours. Dilute the reaction mixture with water and wash with ethyl acetate. Discard the organic layer. Adjust the aqueous phase to pH=2 with 1N hydrochloric acid and extract with ethyl acetate. Dry the organic phase over magnesium sulfate, filter and concentrate to dryness to yield the title compound as a white solid (250 mg, 66%). MS (m/z): 442 (M+1), 464 (M+23).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][C:3]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Cl.[CH3:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH2:39][NH2:40])=[N:37][CH:38]=1)(=[O:32])=[O:31].O>C(#N)C>[CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([NH:40][CH2:39][C:36]2[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:38][N:37]=2)=[O:21])=[CH:4][C:3]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 96 %

Procedure:
6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (52.0 kg, 1 mol eq, limiting reagent) and acetonitrile (208 L, 4 rel vol,) were charged. The reaction mixture was heated to 50° C. 1,1′-s carbonyldiimidazole as a solution in acetonitrile (208 L, 4 rel vol) is charged to the reaction until the reaction is complete as judged by HPLC. C-(5-(Methanesulfonyl)pyridine-2-yl)methylamine monohydrochloride (33.8 kg, 1.1 mol eq) was charged and the reaction maintained at 50° C. until the reaction was deemed complete as judged by HPLC. Water (780 L, 15 rel vol) was charged. The reaction mixture was stirred, cooled and further stirred. The solid was collected by filtration and washed twice with water (2×104 L, 2×2 rel vol) and dried to constant weight to yield the title compound (96.0 kg, 176.0 mol, 96%); 1H NMR (d6-DMSO): δ 1.83 (s, 3H); 3.29 (s, 3H); 3.72 (s, 3H); 4.73 (d, 2H, J 5.8 Hz); 6.33 (d, 1H, J=1.9 Hz); 7.53 (d, 1H, J=1.9 Hz); 7.57 (d, 1H, J 8.3 Hz); 7.81-7.88 (m, 2H); 7.92-7.94 (m, 1H); 8.03 (s, 1H); 8.21 (s, 1H); 8.27 (dd, 1H, J 2.3, 7.9 Hz); 8.99 (d, 1H, J=2.3 Hz); 10.06 (t, 1H, J 6.0 Hz); LCMS: m/z 546.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[S:12])=[C:30]([CH3:35])[C:29]=1[CH3:36]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+]>CO.[Cu]>[CH3:9][O:10][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1
Reactant: C[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1cncc(Br)c1
Temperature: 150 °C
Yield: 59.2 %

Procedure:
A mixture of 3,5-dibromopyridine (20.00 g, 84.42 mmol), sodium methoxide (11.40 g, 211.06 mmol), and copper powder (1 g, 5% by weight of 3,5-dibromopyridine) in dry methanol was heated in a sealed glass tube at 150° C. for 14 h. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4×200 mL). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (1:9, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing 9.40 g (59.5%) of a colorless oil, which tended to crystallize upon cooling.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([NH:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.5 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (144 mg) in THF (1.5 ml) were added triethylamine (0.08 mL) and acetyl chloride (45 mg), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (177 mg).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].C([O:12][C:13](=[S:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18](Cl)[CH2:19][CH2:20][CH3:21])C.[OH-].[K+].Cl>O>[CH2:1]([S:8][CH:18]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([OH:12])=[S:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CCCC(Cl)CCCCC(=S)OCC
Agent: Cl
Agent: [K+]
Agent: [Na]
Solvent: O
Product: CCCC(CCCCC(O)=S)SCc1ccccc1
Reaction time: 0.5 h

Procedure:
12.4 grams (0.1 mole) of benzyl mercaptan were added to a solution of 2.3 grams of sodium in 75 ml of water free ethanol (corresponding to 0.1 mole of sodium ethanolate) and the mixture stirred for 0.5 hour at +10° C. Thereupon there were added 22.72 grams (0.09 mole) of 6-chloro-8-methylthiooctanoic acid ethyl ester (X) and the mixture heated for 20 hours at reflux. To the cooled reaction mixture there were added 11.2 grams (0.17 mole) of potassium hydroxide and stirring was carried out for 20 hours at room temperature. After addition of 500 ml of water the mixture was acidified with dilute hydrochloric acid, extracted with dichloromethane, the combined extracts washed with saturated aqueous sodium chloride solution and dried with sodium sulfate. By distilling off the solvent in a vacuum there were obtained 28.0 grams (96% of theory) of crude b 6-benzylthio-8-methylthiooctanoic acid.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:9]2[N:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:12]=[C:13]([CH3:14])[C:8]=2[CH:7]=[C:6]([C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[C:5]1=[O:40])[CH3:3]>O1CCOCC1.CO>[CH2:2]([N:4]1[C:9]2[N:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:18][CH:17]=3)[N:12]=[C:13]([CH3:14])[C:8]=2[CH:7]=[C:6]([C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[C:5]1=[O:40])[CH3:3]
Reactant: CCn1c(=O)c(-c2nccs2)cc2c(C)nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCn1c(=O)c(-c2nccs2)cc2c(C)nc(Nc3ccc(N4CCNCC4)cc3)nc21
Yield: 74.1 %

Procedure:
A solution of 4M HCl in dioxane (3 mL) was added to a solution of tert-butyl 4-(4-(8-ethyl-4-methyl-7-oxo-6-(thiazol-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl)piperazine-1-carboxylate (99 mg, 0.181 mmol) in anhydrous methanol. After one h, a precipitate formed which was collected by vacuum filtration and identified as 8-ethyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (60 mg, 74% yield) as the HCl salt; MS calculated for C23H25N7OS.HCl: 447.5645, MS (EI) observed 448.1 (MH+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[C:2]=[O:3].[CH3:18][N:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[C:22]=2[CH:21]=[N:20]1.N1C2C=CC=C(N)C=2C=N1>>[N:11]1([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][NH:1][C:2]([NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:22]=3[CH:21]=[N:20][N:19]4[CH3:18])=[O:3])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NCc1ccc(N2CCCCCC2)cc1
Reactant: Cn1ncc2c(N)cccc21
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCCC4)cc3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]azepane and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 8.97 (s, 1H), 8.18 (s, 1H), 7.65 (d, 1H), 7.14 (m, 4H), 7.11 (d, 1H), 6.95 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.27 (m, 4H), 1.90 (m, 4H), 1.53 (m, 4H); MS (ESI) (M+H)+378.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH2:19]([CH:21]([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22])[CH3:20].CO>CCCCCCC>[CH3:28][C:26]1[O:25][N:24]=[C:23]([CH:21]([NH:22][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:19][CH3:20])[N:27]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CCC(N)c1noc(C)n1
Agent: Cl
Solvent: CCCCCCC
Solvent: CO
Product: CCC(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1noc(C)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-ethyl-5-methyl-1,2,4-oxadiazole-3-methanamine hydrochloride (1:1) (CAN 111997-68-3) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 357.1913 (M+H)+, αD20 (MeOH)=−35.1°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:5]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:18][CH:17]([CH3:19])[CH:12]([N:6]1[C:5](=[O:20])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[CH:3]=2)[C:7]1=[O:11])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C(C)C)N1C(=O)c2ccc(Br)cc2C1=O
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(C)C)N1C(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Temperature: 80 °C

Procedure:
The compound of example 660 (2.5 g, 7.35 mmol); 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (2.19 g, 8.82 mmol) and bis-Pinacolato diborane (180 mg, 0.22 mmol) were taken in dry DMF under argon atmosphere. Degassed 2M solution of sodium carbonate (1.94 g, 18.37 mmol) was added and the reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled and the solvent was removed by distillation. The residue was taken in water and this aqueous mixture was extracted with ethyl acetate. The crude material was purified through column chromatography (silicagel, 30% dichloromethane in petroleum ether) to afford the title compound.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:11]([O:26][CH3:27])[CH:10]=1.COCCCOC1C=CC(C(CCCCC)CC(O)=O)=C(OC)C=1>CO.C(OCC)(=O)C>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:11]([O:26][CH3:27])[CH:10]=1
Reactant: C[S-]
Reactant: CCCCCC(CC(=O)OC)c1ccc(OCCCBr)cc1OC
Agent: CCCCCC(CC(=O)O)c1ccc(OCCCOC)cc1OC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCC(CC(=O)OC)c1ccc(OCCCSC)cc1OC
Yield: 83 %

Procedure:
200 mg (2.85 mmol) of sodium thiomethoxide were added to a solution of 278 mg (0.69 mmol) of methyl 3-[4-(3-bromopropoxy)-2-methoxyphenyl]octanoate, which was a synthetic intermediate of the compound of Preparation 50A, in 6 ml of methanol, and the resulting mixture was stirred for 1 hour. The reaction mixture was then diluted with ethyl acetate, and the diluted solution was washed several times with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give methyl 3-[4-(3-methylthiopropoxy)-2-methoxyphenyl]octanoate containing a small amount of impurities. Oxidation of the product and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Example 21 to give 230 mg of the sulfone derivative as an oily substance in a 83% yield over the two steps. This product was hydrolyzed in a similar manner to that described in Preparation 7 to give the title compound as an oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)([O-])=O.O.NN>[Ni].C(O)C.CO>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-n2cncn2)nc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCO
Product: Nc1ccc(-n2cncn2)nc1

Procedure:
Raney nickel (0.650 g) was added to a solution of 5-nitro-2-(1H-1,2,4-triazol-1-yl)pyridine (3.2 g, 16.7 mmol) in a mixture of ethanol and methanol (1:1) (150 mL) followed by the addition of Hydrazine hydrate (2.51 g, 50.2 mmol) and stirring was continued at 25° C. 1 hr. The reaction mixture was filtered over celite bed and washed with methanol. The filtrate and the washings were concentrated under reduced pressure to afford title compound as pale brown liquid. MS (ESI): m/z 162.1 (M+H).
Reaction SMILES: Br[C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[CH:26]([B-](F)(F)F)=[CH2:27].[K+].O>C(O)CC>[CH3:25][O:24][C:23]1[C:2]([CH:26]=[CH2:27])=[CH:3][C:4]2[C:16](=[O:17])[C:15]3[C:14]4[C:9](=[CH:10][C:11]([C:18]#[N:19])=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]([CH3:20])([CH3:21])[C:5]=2[CH:22]=1
Reactant: C=C[B-](F)(F)F
Reactant: COc1cc2c(cc1Br)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: C=Cc1cc2c(cc1OC)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 60 °C
Reaction time: 120 h
Yield: 56.2 %

Procedure:
9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 50 mg, 0.13 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (1:1) (10.3 mg, 0.1 eq.), TEA (53 μl, 3 eq.) and potassium vinyltrifluoroborate (51 mg, 3 eq.) were dissolved in n-propanol and the mixture was stirred at 60° C. for 5 days. The reaction solution was added to water and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (brown powder, 25 mg, 19%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](CO)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(C[O:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[CH:30][NH:31]3)C1)=O)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[CH:30][NH:31]2)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CC(C)(C)OC(=O)N1CC(COc2cccc3[nH]ccc23)C1
Product: CN(CCOc1cccc2[nH]ccc12)C(=O)OC(C)(C)C

Procedure:
In a similar manner, using 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester in place of (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester, 3-(1H-Indol-4-yloxymethyl)-azetidine-1-carboxylic acid tert-butyl ester was prepared, (25%), (M−H)−=301.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:36][CH2:37][CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]([CH2:36][CH2:37][CH3:38])=[N:10][C:11]=3[CH:16]=2)(=[O:27])=[O:28])=[CH:30][CH:31]=1
Reactant: CCCc1nc2cc(N(Cc3cccc(F)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3cccc(F)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(4-Fluoro-benzenesulfonyl)-(3-fluoro-benzyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. MS calculated for C25H23F2N3O4S—H: 498, observed: 498.
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C(#N)C.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 21 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (726 mg, 2.76 mmol), 4-nitrobenzoic acid (462 mg, 2.76 mmol), and acetonitrile (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in acetonitrile (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 21 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml,×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 10% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (349 mg, yield: 54%/(S)-2-octanol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[C:3]([CH3:10])=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Cc1c(N)cccc1C#N
Agent: Br
Product: Cc1c(C#N)cccc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 56.5 %

Procedure:
3-amino-2-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-cyano-2-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (52 mg, 55%) as a white solid. Mass Spectrum: M+H+ 461.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC#N>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC#N
Product: C[C@H](Nc1cc(Cl)ncn1)c1ccccc1
Yield: 79.6 %

Procedure:
A solution of 4,6-dichloropyrimidine (14.9 g, 100 mmole) and (1S)-1-phenylethylamine (13.3 g, 110 mmole) in CH3CN (100 mL) was refluxed for 4 hours. The reaction was partitioned between Et2O (500 mL) and H2O (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel 60 with Hexane/EtOAc 3:1. Pure fractions were combined, concentrated under reduced pressure, and dried under high vacuum to afford the titled compound (18.6 g, 80%) as a yellow oil. 1H NMR (CDCl3): δ 1.57 (d, J=7.0 Hz, 3H), 4.6 (b s,1H), 5.6 (b s,1H), 6.19 (s,1H), 7.34 (m, 5H), 8.30 (s,1H); LC/MS (MH+) 233.62.