Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:4]=1[CH:5]([CH3:16])[NH:6][C:7](SC)=[N:8]2.[O:17]([CH2:24][CH2:25][NH2:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>C(#N)C.OO.O>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:4]=1[CH:5]([CH3:16])[NH:6][C:7]([NH:26][CH2:25][CH2:24][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:8]2
Reactant: NCCOc1ccccc1
Reactant: CSC1=Nc2c(Cl)ccc(Cl)c2C(C)N1
Agent: I
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1NC(NCCOc2ccccc2)=Nc2c(Cl)ccc(Cl)c21
Temperature: 170 °C
Yield: 93.3 %

Procedure:
5,8-Dichloro-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (116 mg, 0.30 mmol) and 2-phenoxyethyl amine (126 mg, 0.9 mmol) were dissolved in acetonitrile (0.9 ml) and heated to 170° C. in a sealed tube in a microwave oven for 30 minutes. After cooling the reaction was treated with 1N aqueous sodium hydroxide solution (0.9 ml) and 5 to 7 drops of 30% aqueous hydrogen peroxide solution. The reaction was diluted with water and the product precipitated as a white solid, which was filtered off, washed with water and dried in vacuo to yield the title compound (98 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[Cl:10]N1C(=O)CCC1=O.ClNC1C=CC(C#N)=CN=1>C(#N)C>[NH2:1][C:2]1[C:7]([Cl:10])=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C1CCC(=O)N1Cl
Agent: N#Cc1ccc(NCl)nc1
Solvent: CC#N
Product: N#Cc1cnc(N)c(Cl)c1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 6.0 g (0.05 mol) of 2-amino-5-cyanopyridine, 8.3 g (0.0625 mol) of N-chlorosuccinimide and 200 g of acetonitrile were added, and the reaction was conducted at 50° C. for one hour with stirring. During the reaction, the reaction product was analyzed by liquid chromatography, whereby formation of 2-chloroamino-5-cyanopyridine was confirmed. After completion of the reaction, acetonitrile was distilled off. To separate succinimide and the desired product, 50 g of water was added to the remaining product, and the mixture was stirred. Precipitated crystals were collected by filtration, washed with 50 g of toluene and dried to obtain 6.9 g of 2-amino-3-chloro-5-cyanopyridine as slightly brown crystals (purity as measured by liquid chromatography: 98%, yield: 88%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[NH2:22]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 80 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-tert-butyl 2-(hydrazinecarbonyl)piperidine-1-carboxylate (634 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6), 567 mg of the title compound was afforded (yield 80%).
Reaction SMILES: C1(C)C=CC(S([N:10]=[N+:11]=[N-])(=O)=O)=CC=1.[CH3:14][O:15][C:16]([C@@H:19]1[C:22](=[O:23])[NH:21][C@@H:20]1[CH2:24][C:25](=[O:40])[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[N+:10](=[C:26]([C:25](=[O:40])[CH2:24][C@@H:20]1[C@H:19]([C:16]([O:15][CH3:14])([CH3:18])[CH3:17])[C:22](=[O:23])[NH:21]1)[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])=[N-:11]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
A solution of p-toluenesulfonyl azide (470 mg) in acetonitrile (4.23 ml) was added to a solution of 4-nitrobenzyl 4-[(2R,3R)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]-3-oxobutanoate (752 mg) in acetonitrile (15.04 ml) at 0° C. After stirring at 0° C. for 10 minutes, a solution of triethylamine (0.997 ml) in acetonitrile (8.973 ml) was added dropwise thereto. After stirring at 0° C. for an additional 50 minutes, the reaction mixture was evaporated. The residue was chromatographed on silica gel (11 g) eluting with 0-50% ethyl acetate in methylene chloride to give 4-nitrobenzyl 2-diazo-4-[(2R,3R)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]-3-oxobutanoate (733 mg).
Reaction SMILES: [C:1]([O-:9])([O-])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2].O[C:11]([CH2:15][CH2:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19])([CH:13]=[CH2:14])[CH3:12].C1(C=CC(O)=CC=1)O>C(O)CCC>[CH2:14]([CH2:2][C:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:9])[CH:13]=[C:11]([CH2:15][CH2:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[CH3:19])[CH3:12]
Reactant: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Reactant: CCCCOC(C)([O-])[O-]
Agent: Oc1ccc(O)cc1
Solvent: CCCCO
Product: CCCCOC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
Following the same procedures as in Example 26, a mixture of 1184 g. of n-butyl orthoacetate, 220 g. of nerolidol and 22 g. of hydroquinone was reacted with heating at 160° - 165° C., with removal of n-butanol produced from the reaction system. The reaction mixture was directly distilled in vacuo to give 598 g of n-butyl farnesylacetate, b.p. 134° - 142° C. (0.3 mmHg). Then, this product was fractionated through a rectifying column with 40 numbers of theoretical plates reflux ratio of 20 to give 147.5 g of n-butylΔ 4,8 -trans-farnesylacetate, b.p. 140° - 142° C. (0.3 mmHg). 64% of Δ4,8 -trans-isomer introduced was recovered on distillation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][CH:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)O
Product: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)NCC1CC1
Yield: 44 %

Procedure:
As described for example 90 g, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (99 mg, 0.3 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (51 mg, 44%) which was obtained as an off white solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) and recrystallization from heptane/ethyl acetate. MS: m/e=385.1 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C@H:26]1[CH2:30][CH2:29][C:28](=O)[CH2:27]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:28]3[CH2:29][CH2:30][C@H:26]([CH3:25])[CH2:27]3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C[C@H]1CCC(=O)C1
Solvent: CC(=O)N(C)C
Product: C[C@H]1CCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)C1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.065 g, 0.18 mmol) was reacted with (3S)-3-methylcyclopentanone (0.54 g, 5.6 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 90 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with ethyl acetate/hexane (2:1) and filtered to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:19])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:29](O)=[O:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:29]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:19])[CH:11]=2)=[O:9])[CH:3]=1)=[O:30]
Reactant: O=C(O)CCc1ccccc1Cl
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: Cn1cc(C(=O)c2cncc(NC(=O)CCc3ccccc3Cl)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described above for Example 167 starting from (5-aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 110) and 3-(2-chlorophenyl)propanoic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[N+]([O-])=O)(=[O:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C1(O)C=CC=CC=1.CC(C)([O-])C.[K+]>CN(C=O)C>[F:1][C:2]1[C:3]2[S:9](=[O:11])(=[O:10])[C:12]3[C:17](=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(S(=O)(=O)c2c(O)cccc2F)c([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CC(C)Oc1ccc2c(c1)Oc1cccc(F)c1S2(=O)=O
Yield: 70 %

Procedure:
From 3-fluoro-2-((4-isopropoxy-2-nitrophenyl)sulphonyl)phenol (Example 21): A stirred solution of 3-fluoro-2-((4-isopropoxy-2-nitrophenyl))sulphonyl)phenol (0.35 g, 0.98 mmol) and potassium tert-butoxide (0.13 g, 1.18 mmol) in 25 mL anhydrous DMF was heated at 80° C. for 1 h during which time the reaction color changed from orange to light yellow. After the reaction had been cooled 10% aqueous HCL (100 mL) was added and the mixture extracted with EtOAc (2×100 mL). The combined organics were washed with 10% aqueous HCl (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated in vacuo to a yellow solid (290 mg). Recrystallization from etOAC/hexane gave 210 mg (70%) of the title compound which was identical in all aspects to material prepared from 1-Fluoro-7-isopropoxyphenoxathiin (Example 20).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2ccc([N+](=O)[O-])cc2)c1
Yield: 35 %

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-4-nitro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-9-[2-(4-nitro-phenyl)-ethyl]-9H-purin-6-ylamine: Yield 35%, 1H NMR (DMSO-d6) δ 8.18 (s, 1H), 8.0 (d, J=8.8 Hz, 2H), 7.46 (bs, 2H), 7.26 (d, J=8.8 Hz, 2H), 6.96 (d, J=9.2, 1H), 6.77 (dd, J=8.8, 3.2 Hz, 1H), 6.27 (d, J=3.2 Hz, 1H), 4.50 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.56 (s, 3H), 3.22 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 453.5.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([O:20][CH3:21])=[N:18][C:17]([C:22]([O:24]C)=O)=[CH:16][N:15]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[NH3:33]>>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[C:19]([O:20][CH3:21])=[N:18][C:17]([C:22]([NH2:33])=[O:24])=[CH:16][N:15]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: N
Reactant: COC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(OC)n1
Product: COc1nc(C(N)=O)cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12

Procedure:
A solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-8-methoxy-3-phenylimidazo-[1,2-a]pyrazine-6-carboxylate [Example 7] (65 mg, 0.09 mmol, 80% purity (UPLC area-%), 1.0 eq) in 1.73 mL ammonia (7 M solution in methanol, ˜100 eq) was heated to 130° C. for 2 h in a single mode microwave oven. The volatile components were removed by the use of a rotary evaporator. The solvent was using a rotary evaporator and the crude material was purified via MPLC (Biotage Isolera, 10 g Snap-cartridge; eluent: DCM→DCM/ethanol (8/2)) to deliver 22 mg (43%) of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[C:31]3[N:32]=[C:15]([CH:16]=[CH:17][N:18]3[N:19]=[CH:20]1)[N:14]1[C@@H:10]2[CH2:11][CH2:12][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:6][C:7]1[CH:8]=[C:9]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24][N:23]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C:21]1=[C:31]3[N:32]=[C:15]([CH:16]=[CH:17][N:18]3[N:19]=[CH:20]1)[N:14]1[C@@H:10]2[CH2:11][CH2:12][CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCCO2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Methanesulfonyl chloride (1.69 μL, 0.0218 mmol) was added to a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.02,6.07,12.022,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaene (Example 24, 4.0 mg, 0.0109 mmol), followed by DIEA (9.48 μL, 0.0544 mmol). The reaction was stirred at ambient temperature overnight, concentrated and purified by reverse-phase column chromatography eluting with 0-80% acetonitrile/H2O to afford the title compound (2.9 mg, 59.8% yield). MS (apci) m/z=446.3 (M+H).
Reaction SMILES: [OH-].[K+].CO.O.C([O:9][CH:10]([CH:17]=[CH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C>>[CH:17]([CH:10]([OH:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:18]
Reactant: C=CC(OC(C)=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A second 12 L flask equipped with mechanical stirrer, condensor, and thermocouple was charged with 761.0 g (13.56 mol) KOH (potassium hydroxide), 3.5 L (86.6 mol) of MeOH (methanol), 1.1 L (58.38 mol) of water, and 703 g of vinylbenzyl acetate from the previous step producing a dark red-colored solution. The reaction was heated to reflux and followed by TLC, which indicated that the reaction was complete after 1 hour. The reaction mixture was cooled to room temperature and extracted twice with 4 L of diethyl ether. The ether layer was then washed with three times with 4 L of aqueous sodium chloride, then two times with 4 L of water. The ether layer was dried with MgSO4 (magnesium sulfate) and filtered. Ether was removed from the filtrate under reduced pressure to give a brown oil. (487.0 g, 91% yield) (94% overall). 1H NMR (DMSO-d6): δ 7.35 (m, 4H, aromatic), δ 6.70 (m, 1H, vinyl), δ 5.75 (d, 1H, vinyl), δ 5.25 (d, 1H, vinyl), δ 4.65 (d, 2H, benzyl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH2:25]>O1CCCC1>[CH3:1][O:2][C:3]([CH:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:10]1)[CH2:25][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH2:23])=[O:21]
Reactant: COC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=C(CBr)c1ccccc1
Solvent: C1CCOC1
Product: C=C(CC(C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77.9 %

Procedure:
Lithium hexamethyldisilylazide (1.0 M in THF; 7.31 mL, 7.31 mmol) was added to solution of benzyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1.94 g, 6.65 mmol) in tetrahydrofuran (35 mL) at −78° C. After 40 min, [1-(bromomethyl)vinyl]benzene (1.08 mL, 7.31 mmol) was added and the reaction mixture was warmed to ambient temperature. After 18 h, the mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→40% hexanes/ethyl acetate) gave the title compound (2.11 g). MS 408.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[BH4-].[Na+].O.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(=O)c1ccc(Br)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1ccc(Br)cn1
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)ethanone (5 g, 25 mmol) in anhydrous ethanol (100 mL) was added sodium borohydride (2.85 g, 75 mmol) at room temperature. After 2 hours, water (10 mL) was added to quench the reaction at 0° C. and then saturated hydrochloric acid aqueous (10 mL) was added the mixture to adjust pH to 7. The mixture was extracted with ethyl acetate (50 mL). The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give 1-(5-bromopyridin-2-yl)ethanol (3 g, 60%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[C:36]2[C:43]([I:44])=[CH:42][NH:41][C:37]=2[N:38]=[CH:39][N:40]=1.[Si:45]([O:62][CH2:63][C@@H:64]1[CH2:68][C@@H:67](O)[CH2:66][N:65]1[C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])([C:58]([CH3:61])([CH3:60])[CH3:59])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1COCC1.O.C(OCC)(=O)C>[Si:45]([O:62][CH2:63][C@@H:64]1[CH2:68][C@H:67]([N:41]2[C:37]3[N:38]=[CH:39][N:40]=[C:35]([Cl:34])[C:36]=3[C:43]([I:44])=[CH:42]2)[CH2:66][N:65]1[C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])([C:58]([CH3:60])([CH3:61])[CH3:59])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of triphenylphosphine (443 mg) in THF (25 ml) was cooled to 0° C., and DIAD (340 μl) was added thereto dropwise. The reaction mixture was stirred at 0° C. for 1 hour. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (363 mg) and the (2S,4R)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (651.6 mg) obtained in Example 28 (Step 1) were added thereto, and stirred at room temperature overnight. Ethyl acetate and water were added to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (400 mg). m/z [M+H]+ 718.5
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][CH2:15][C@@:16]([OH:28])([CH3:27])[CH2:17][N:18]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[N:20]=[C:19]1Cl)=[O:13])[CH2:6][CH2:5]2.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][CH2:15][C@:16]1([CH3:27])[O:28][C:19]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:18]3[CH2:17]1)=[O:13])[CH2:6][CH2:5]2
Reactant: C[C@](O)(COC(=O)N1CCc2cc(Cl)ccc2C1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CCc3cc(Cl)ccc3C2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate prepared in Example 115 (0.26 g, 0.61 mmol) in DMF (2 ml), sodium hydride (30 mg, 0.73 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice-water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, concentrated under reduced pressure and recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 6-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylate (0.12 g, 49%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.[NH:18](/[C:22](/[CH3:28])=[CH:23]\[C:24](OC)=[O:25])[C:19]([CH3:21])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:28])[N:18]=[C:19]2[CH3:21])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 3-fluoro-4-(pyrrolidin-1-yl)aniline (0.50 g, 2.78 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (14 mL, 14 mmol, 1 M in heptane) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (480 mg, 3.06 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (300 mg, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[N:14]([CH2:29][CH2:30][CH3:31])[C:13]=2[CH:32]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[N:14]([CH2:29][CH2:30][CH3:31])[C:13]=2[CH:32]=1)[CH2:39][C:35]1[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2n1CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
The compound (8.8 mg) obtained in Example 48-6 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (2.6 mg) and sodium cyanoborohydride (2.5 mg). After the solution was adjusted to pH 4 with acetic acid, the whole was stirred at room temperature for 18 hours. After the solvent was distilled off, the resultant was neutralized with a saturated aqueous sodium hydrogen carbonate solution and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (9.3 mg) of the subject compound as a white solid.