Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:6]=1.Cl[C:31]([F:36])([F:35])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:31]([F:36])[F:35])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:26])[F:27])[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
{4-Hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.40 g, 0.92 mmol), sodium chlorodifluoroacetate (0.282 g, 1.86 mmol), and potassium carbonate (0.14 g, 1.02 mmol) were combined in DMF:H2O (8.5:1; 4.6 mL) and degassed with N2 for 15 minutes. The reaction was then stirred at 100° C. for 4 hours. After work-up with EtOAc and 1N aqueous HCl, the residue was purified by silica gel chromatography to give {4-difluoromethoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1.[H-].[Na+].S(OCC)(O[CH2:29][CH3:30])(=O)=O>CN(C=O)C.O>[CH2:29]([N:12]1[C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:11]1[CH3:16])[CH3:30]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CC(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)=C1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
The product from Example 5, Step 1 (0.627 g, 2.00 mmol, 1.00 equiv) was dissolved in DMF (9 mL) and sodium hydride (60% dispersion in mineral oil, 0.112 g, 1.40 equiv) was added. After the reaction had stirred for 20 minutes at room temperature, diethyl sulfate (0.314 mL, 2.40 mmol, 1.20 equiv) was added and the reaction was heated to 100° C. for 4 hours. The reaction was diluted with H2O and extracted with EtOAc. The organic phase was washed four times with H2O and once with satd. NaCl, dried over MgSO4 and concentrated en vacuo to provide 0.627 g (92%) of the title compound as an oil. MS (ES+) m/e 342 [M+H]+
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O.C(O)(=O)C>[C:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CC(=O)N1CCN(Cc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
4-phenoxybenzaldehyde (989 mg) and 1-acetylpiperazine (713 mg) were dissolved in 1,2-dichloroethane (11 ml), and sodium triacetoxyboro hydride (1.60 g) and acetic acid (300 mg) were added. The atmosphere was replaced with argon and the mixture was stirred at room temperature for 7 hours. Water (5 ml) and aqueous saturated sodium hydrogen carbonate solution (20 ml) were added and the mixture was extracted 5 times with chloroform. Organic layers were combined and dried over anhydrous sodium sulfate. Chloroform was removed and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=20:1-10:1) to quantitatively obtain 1.55 g of 1-acetyl-4-(4-phenoxybenzyl)piperazine.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:48][C:49]1[CH:50]=[C:51]([S:55][C:56]2[C:61](O)=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:52]=[CH:53][CH:54]=1>C1COCC1>[Br:48][C:49]1[CH:50]=[C:51]([S:55][C:56]2[C:61]([O:14][CH2:13][CH2:12][CH2:11][C:10]3[CH:9]=[CH:8][N:7]=[CH:6][C:5]=3[OH:4])=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: Oc1cccnc1Sc1cccc(Br)c1
Reactant: COCOc1cnccc1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1cnccc1CCCOc1cccnc1Sc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (1.59 g, 9.2 mmol) obtained in Example 2 and triphenylphosphine (2.78 g, 10.6 mmol) are dissolved in THF (40 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (1.85 g, 9.2 mmol) and 2-(3-bromophenylthio)-3-pyridinol (2.00 g, 7.1 mmol) obtained in Reference Example 1 under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (200 ml) and a 15% aqueous hydrochloric acid solution (10 ml), and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/ethyl acetate), and further recrystallized from diethyl ether to give the title compound (1.98 g) as colorless crystals, m.p. 169-171° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][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][CH3:26])[C:5]=1[CH:6]=O)[CH3:2].[C:27]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:28][C:29]([CH3:31])=O.C(O)(=O)C.N1CCCCC1.[CH3:46][CH2:47][O:48][C:49](/[CH:51]=[C:52](\[NH2:54])/[CH3:53])=[O:50]>C(O)CCC>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][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][CH3:26])[C:5]=1[CH:6]1[C:28]([C:27]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([CH3:31])[NH:54][C:52]([CH3:53])=[C:51]1[C:49]([O:48][CH2:47][CH3:46])=[O:50])[CH3:2]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C=O
Reactant: CCOC(=O)CC(C)=O
Solvent: CCCCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C1C(C(=O)OCC)=C(C)NC(C)=C1C(=O)OCC
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and ethyl acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecyl phenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate as white powder.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12](O)[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.ClCC(Cl)(Cl)Cl.P(Br)(Br)([Br:24])=O.[OH-].[Na+]>C(OCC)C>[F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([Br:24])[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1O
Agent: ClCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cn1nc(-c2ncc(Cl)cc2F)cc1Br
Temperature: 130 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
20.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-hydroxy-1-methyl-[1H]-pyrazole (Example H14) are initially introduced into 80 ml of tetrachloroethane. A total of 25.2 g of phosphorus oxybromide (POBr3) are added in portions to the brown suspension and the mixture is then stirred at a temperature of 130° C. for 2 hours. Thereafter, it is cooled and 150 ml of a 2 molar sodium hydroxide solution are added dropwise, while cooling with an ice-bath. After addition of diethyl ether and separation of the phases, the organic phase is washed successively with water, dilute hydrochloric acid and brine, dried over sodium sulfate, filtered and concentrated in vacuo. 19.94 g of a brown solid are obtained as the crude product, and this solid is purified by means of digestion with 50 ml of n-hexane. 12.65 g of the desired title compound are obtained as a brown solid of melting point 110-111° C.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[N:29]=[C:28]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].[N:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]1[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[C:35]1([CH3:38])[CH:34]=[CH:33][C:32]([C:30]2[N:29]=[C:28]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)[N:27]=[C:26]([C:21]3[CH:20]=[C:19]([C:61]4[CH:60]=[CH:59][C:58]([C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][N:52]=5)=[CH:63][CH:62]=4)[CH:24]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:22]=3)[N:31]=2)=[CH:37][CH:36]=1
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(Br)cc(Br)c3)n2)cc1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(-c4ccc(-c5ccccn5)cc4)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
In a stream of argon, 0.538 g (2.42 mmol) of 9-phenanthreneboronic acid, 1.20 g (2.42 mmol) of 2-(3,5-dibromophenyl)-4,6-di-p-tolyl-1,3,5-triazine and 28.0 mg (0.0242 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 90 mL of toluene and 10 mL of ethanol, and the resultant suspension was heated to 50° C. To the suspension, 7.26 mL (7.26 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 3 hours. The resultant reaction mixture was cooled to room temperature, and then, 0.722 g (3.63 mmol) of 4-(2-pyridyl)phenylboronic acid and 7.26 mL (7.26 mmol) of an aqueous 1M K2CO3 solution were added to the reaction mixture. The resultant mixture was heated to 60° C., and maintained at that temperature for 15 hours while being stirred. The obtained reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 0.680 g of the target 4,6-di-p-tolyl-2-[5-(9-phenanthryl)-4′-(2-pyridyl)biphenyl-3-yl]-1,3,5-triazine as a white solid (yield: 42%).
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[C:34]([C:36]2[C:41]([I:42])=[CH:40][C:39]([I:43])=[CH:38][C:37]=2[I:44])[CH:33]=[CH:32][C:5]=1[C:6]([C:8]1([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:13]1[NH2:14])[O:9]C(=O)C)=[O:7])([O-])=O.Cl>>[NH2:1][C:4]1[CH:35]=[C:34]([C:36]2[C:37]([I:44])=[CH:38][C:39]([I:43])=[CH:40][C:41]=2[I:42])[CH:33]=[CH:32][C:5]=1[C:6]([C:8]1([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:13]1[NH2:14])[OH:9])=[O:7]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)(C(=O)c2ccc(-c3c(I)cc(I)cc3I)cc2[N+](=O)[O-])[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Product: Nc1cc(-c2c(I)cc(I)cc2I)ccc1C(=O)C1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N

Procedure:
2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10) is treat with stannous chloride in the presence of hydrochloric acid to yield 2-amino-4-(2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (11).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cccc(-c2cccc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(-c2cccc(-c3ccc(C(C)C)cc3)n2)c1
Temperature: 80 °C
Yield: 69.5 %

Procedure:
Part B. A solution of ethyl 3-(6-bromo-pyridin-2-yl)-benzoate (154 mg, 0.5 mmol) and 4-isopropylbenzeneboronic acid (83 mg, 0.5 mmol) in acetonitrile is treated with a solution of sodium carbonate (160 mg) in water (1 mL). The mixture is degassed twice, and a catalytic amount of tetrakis(triphenylphosphine)palladium is added under the protection of nitrogen. The reaction mixture is stirred at 80° C. until the consumption of starting material is observed by TLC. The mixture is cooled, filtered and evaporated, and the residual material is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate, filtered and evaporated. The residue is purified by column chromatography to afford ethyl 3-[6-(4-isopropyl-phenyl)-pyridin-2-yl]-benzoate (120 mg, 69%).
Reaction SMILES: CO[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]1([C:4](=[CH:3][S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: COC=C(C(=O)OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(=CSc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2.0 g (10.4 mmol) of methyl 3-methoxy-2-phenyl-2-propenoate 1.26 g (11.4 mmol) of thiophenol and 10 mg of p-toluenesulfonic acid monohydrate in 28 ml of toluene was stirred at 90° C. for 9 hours. The reaction mixture was cooled to room temperature and then concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 1.75 g of methyl 2-phenyl-3-(phenylthio)-2-propenoate.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2C=C[C:17]([NH2:20])=[C:16]([N+:21]([O-])=O)[CH2:15]2)=[CH:10][CH:9]=1)#[N:7].[CH2:24](O)[CH3:25]>O>[NH2:21][C:16]1[CH:17]=[N:20][CH:24]=[CH:25][C:15]=1[NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(N2C=CC(N)=C([N+](=O)[O-])C2)cc1
Reactant: CCO
Agent: Cl[Sn]Cl
Solvent: O
Product: N#Cc1ccc(Nc2ccncc2N)cc1
Temperature: 0 °C

Procedure:
According to a modification of the method of Pharm. Helv. Acta, 1975, 50, 188., tin dichloride dihydrate (56.4 g, 250 mmol) was added to a suspension of N-(4-cyanophenyl)-4-amino-3-nitropyridine (12.0 g, 50 mmol) in 2N aqueous hydrocholoric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated to reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium hydroxide (400 ml) and filtered. The creamy-coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator. The product, 3-amino-4-(4'-cyanophenyl)aminopyridine, 9.31 g, gradually turns reddish brown on exposure to light and air.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[N:6][N:7]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])[CH2:13]2)=[O:11])[CH:8]=1)[CH2:2][CH3:3].O.[OH-].[Li+]>CO.O>[CH2:1]([C:4]1[N:5]=[N:6][N:7]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([C:18]([OH:20])=[O:19])[CH2:13]2)=[O:11])[CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1cn(CC(=O)N2CCOC(C(=O)OCc3ccccc3)C2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1cn(CC(=O)N2CCOC(C(=O)O)C2)nn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In a 25-mL RBF, benzyl 4-(2-(4-propyl-1H-1,2,3-triazol-1-yl)acetyl)morpholine-2-carboxylate (0.105 g, 0.282 mmol) was taken up in MeOH (1.0 mL). Lithium hydroxide hydrate (0.0130 g, 0.310 mmol) was added as a solution in water (1.0 mL). The mixture was stirred at ambient temperature for 14 h, then concentrated, and used crude in the subsequent step. MS m/z 283 (M+1).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1.[CH2:13]=O.[BH3-][C:16]#[N:17].[Na+]>CO.CC(O)=O>[CH3:13][N:17]([CH3:16])[C:4]1[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=[CH:2][CH:3]=1
Reactant: COC(=O)Cc1ccc(N)cn1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1ncccc1N(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of methyl 2-(5-aminopyridin-2-yl)acetate (600 mg, 3.6 mmol) and paraformaldehyde (578.3 mg, 19.3 mmol) in methanol (20 mL) was added NaBH3CN (1.2 g, 19.3 mmol) and AcOH (1 drop, cat.). The mixture was stirred at room temperature for 12 h. Then, the reaction was quenched with aqueous ammonium chloride and extracted with DCM. The organic layer was with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to get desired product. LC-MS: m/z (M+H)=195.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]#[N:15])=[CH:4][CH:3]=1.Cl.[NH2:17][C:18]([CH3:27])([CH3:26])[C:19](OC(C)(C)C)=[O:20].[C:28](Cl)(Cl)=[O:29]>>[CH3:27][C:18]1([CH3:26])[C:19](=[O:20])[N:1]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([C:14]#[N:15])=[CH:4][CH:3]=2)[C:28](=[O:29])[NH:17]1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: N#Cc1ccc(N)cc1-c1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(-c3ccccc3)c2)C1=O

Procedure:
Compound 223.1 was prepared by the process as described for 1.1 by reaction of 223.3 with tert-butyl 2-amino-2-methylpropionate hydrochloride and phosgene (solution in toluene). 1H NMR: 8.73, s, 1H; 8.09, d, 1H, 7.75, s, 1H, 7.69, d, 1H, 7.62-7.5, m, 5H, 1.42, s, 6H.
Reaction SMILES: C1[C:6]([C:7](OO)=[O:8])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=[O:18])C1C=CC=CC=1.CO[CH:31]=[CH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH2:7]([O:8][C:32](=[CH2:31])[CH2:33][C:34]12[O:18][CH:39]1[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH3:6]
Reactant: COC=CCc1ccccc1
Reactant: O=C(OO)c1ccccc1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(CC12C=CC=CC1O2)OCC
Reaction time: 72 h
Yield: 41 %

Procedure:
To the chloroform solution containing perbenzoic acid prepared from 29 g of benzoyl peroxide was added 6.5 g of o-methoxyallylbenzene dissolved in 20 ml of chloroform, and the mixture was allowed to stand at 0° - 5° C for 3 days. The resulting mixture was washed with 10% sodium hydroxide solution, Mohr's salt solution and then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 2.9 g (yield 41%) of 2-ethoxyallylbenzene oxide as pale yellow clear liquid having a boiling point of 120° - 121° C/9 mmHg.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[C@@H:29]([OH:39])[C@H:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1.FC(F)(F)C(O)=O.C(NC(=O)NCCCNC(C1N=C2C(N=CN2[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O)C.[CH3:113][N:114]([CH3:118])[C:115](Cl)=[O:116]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:113][N:114]([CH3:118])[C:115](=[O:116])[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[CH:29]([OH:39])[CH:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1
Reactant: NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)CC1
Reactant: CN(C)C(=O)Cl
Agent: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)C(O)C4O)c3n2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (4-amino-cyclohexyl)-amide trifluoroacetate (Example 83, first step a) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid [3-(3-ethyl-ureido)-propyl]-amide trifluoroacetate (Example 87) replacing ethyl isocyanate with dimethylcarbamic chloride.
Reaction SMILES: C(N1C2C(=CC(F)=C(F)C=2F)[C:6](=[O:16])C(C(O)=O)=C1)C.[C:20]([N:24]1[C:33]2[C:28](=[CH:29][C:30]([F:35])=[C:31](Cl)[N:32]=2)[C:27](=[O:36])[C:26]([C:37]([OH:39])=[O:38])=[CH:25]1)([CH3:23])([CH3:22])C.[CH:40]([N:43]([CH2:47]C)[CH:44](C)[CH3:45])(C)[CH3:41]>CO.C(Cl)Cl.CN(C=O)C>[F:35][C:30]1[C:31]([N:32]2[CH2:45][CH2:44][N:43]([CH3:47])[CH2:40][CH2:41]2)=[C:6]2[O:16][CH2:23][CH:20]([CH3:22])[N:24]3[CH:25]=[C:26]([C:37]([OH:39])=[O:38])[C:27](=[O:36])[C:28]([CH:29]=1)=[C:33]23
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C

Procedure:
To a solution of Compound 4 (1.9 g), prepared in the same manner as Compound 5 in Example 11, in a 1:1 mixture of DMF and CH2Cl2 (60 mL) is slowly added a solution of Compound 3 (2.32 g) in a 1:1 mixture of DMF and CH2Cl2 (30 mL), under N2. N,N-Diisopropylethylamine (0.98 mL) is added dropwise and the reaction is allowed to stir at ambient temperature until complete. Upon completion, methanol (15 mL) is added and the mixture is stirred for 15 minutes. The volatiles are removed in vacuo until a small mount of DMF remains whereupon methanol (150 mL) is added. The mixture is stirred for 5 minutes and filtered to obtain Compound 5.