Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.Br[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([F:33])[CH:32]=1)[C:28]#[N:29]>>[C:28]([C:27]1[CH:26]=[C:25]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:32]=[C:31]([F:33])[CH:30]=1)#[N:29]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Reactant: N#Cc1cc(F)cc(Br)c1
Product: CC1=CC(C)(C)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Yield: 38.6 %

Procedure:
This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (46.3 mg, 0.14 mmol) and 3-bromo-5-fluorobenzonitrile (29.1 mg, 0.14 mmol). The crude material was purified by recrystallization from hexane to afford 15.8 mg (37%) of Compound 271. Data for Compound 271: 1H NMR (400 MHz, acetone-d6) 7.83 (app t, J=1.3, 1 H), 7.68 (dd, J=10.6, 4.0, 1 H), 7.43 (d, J=2.0, 1 H), 7.41 (dd, J=2.2, 1.2 1H) 7.35 (dd, J=8.3, 2.2, 1 H), 6.59 (d, J=8.4, 1 H), 5.35 (br s, 1 H), 5.39 (s, 1 H), 2.04 (s, 3 H), 1.28 (s, 6 H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CN(C)C=O.O>[Br:1][C:2]1[N:3]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(Br)c1ccccc1
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(Br)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of methyl 2-bromo-1H-indole-3-carboxylate (1.0 g, 4.0 mmol) in dimethylformamide was added sodium hydride (0.32 g, 8.0 mmol, 60% in oil) under ice bath. The resulting mixture was stirred at room temperature for 0.5 hour. Then (1-bromoethyl)benzene (1.1 g, 6.0 mmol) was added in portion slowly. Then the mixture was stirred at room temperature for 1 hour. After the reaction, it was diluted with water (100 mL), and the product was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by column Chromatography (silica gel: ethyl acetate:petroleum ether=1:8) to give the pure product methyl 2-bromo-1-(1-phenylethyl)-1H-indole-3-carboxylate (1.1 g, 75%) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=[O:19])[C:13]1C=CC=CC=1.C[Si]([C:24]1[NH:29][C:28](=[O:30])[N:27]([Si](C)(C)C)[C:26](=[O:35])[C:25]=1[F:36])(C)C.FC1C(=O)NC(=O)NC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO.C(O)CO>[C:12]([O:8][CH2:9][CH2:10][O:11][CH:7]([N:29]1[CH:24]=[C:25]([F:36])[C:26](=[O:35])[NH:27][C:28]1=[O:30])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:19])[CH3:13]
Reactant: c1ccc(C2OCCO2)cc1
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [Na+]
Solvent: CO
Solvent: OCCO
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCOC(c1ccccc1)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
2-Phenyl-1,3-dioxolan (15 g) prepared from benzaldehyde and ethylene glycol was added to bis(trimethylsilyl)-5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g). Then a solution of anhydrous stannic chloride (6 ml) in chloroform (15 ml) was added dropwise to the mixture over one hour while stirring under cooling in an ice bath. Following stirring at room temperature for one hour, the reaction mixture was poured into methanol (200 ml) containing sodium bicarbonate (40 g) followed by stirring at room temperature for one hour. The precipitate was removed by filtration and the filtrate was evaporated under reduced pressure to dryness. Acetic anhydride (20 ml) and pyridine (20 ml) were added to the residue and the mixture was left to stand at room temperature for 3 hours. The reaction mixture was poured into ice-water, and the resulting oil was extracted with chloroform (100 ml). The chloroform layer was washed with hydrochloric acid and then with water, and evaporated under reduced pressure to remove the solvent. The residue was purified by column chromatography using silica gel and chloroform as the eluent, and treated with methanol to give 6.3 g of crystalline 1-[α-(2-acetoxyethoxy)benzyl]-5-fluorouracil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:15])[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:2]1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)[CH:20]=[C:19]([CH3:29])[N:18]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:12][C:10]([F:13])([F:11])[C@@H:9]([O:8][C:7](=[O:15])[NH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:17]2[N:18]=[C:19]([CH3:29])[CH:20]=[C:21]([NH:23][C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)[N:22]=2)[CH2:2]1)[CH3:14]
Reactant: C[C@H](OC(=O)N[C@H]1CCNC1)C(F)(F)F
Reactant: Cc1cc(Nc2cc[nH]n2)nc(Cl)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc[nH]n2)nc(N2CC[C@H](NC(=O)O[C@@H](C)C(F)(F)F)C2)n1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To a solution of (2S)-1,1,1-trifluoropropan-2-yl (3S)-pyrrolidin-3-ylcarbamate (50 mg) in DMSO (5 ml) was added 2-chloro-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (46 mg) prepared in Referential Example 1 and DIEA (28 mg) at room temperature. The resulting mixture was stirred at 110° C. for 15 hours and then cooled to room temperature. The mixture was purified with preparative RP-HPLC to give (2S)-1,1,1-trifluoropropan-2-yl{(3S)-1-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]pyrrolidin-3-yl}carbamate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][CH:13]([CH2:22][CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.S(=O)(=O)(O)O.B(O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:13]([CH3:12])[CH2:22][CH3:23])=[CH:20][CH:19]=1)=[O:5]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CCC(C)Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CCC(C)Cc1ccc(OC(=O)c2ccc(O)cc2Cl)cc1

Procedure:
This esterficiation may be carried out by the method described by Lowrance (Tet. Lett. 1971, 3453). The reactants (2-chloro-4-hydroxybenzoic acid and (+)4-(2'-methylbutyl)phenol in equimolar amounts) are dissolved in toluene and heated in a Dean and Stark apparatus together with catalytic amounts of sulphuric acid and boric acid. After crystallisation from ethanol/water, the product has the m.p. 142° C.
Reaction SMILES: [NH2-].[Na+].C([O:10][C:11](=O)[C@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.[CH3:55][S:56]([CH3:58])=[O:57]>O1CCCC1>[CH2:14]([N:13]([C@@H:12]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:11](=[O:10])[CH2:55][S:56]([CH3:58])=[O:57])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CS(C)=O
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 74.5 °C
Yield: 85.6 %

Procedure:
3.76 g (96.39 mmol) of sodium amide was suspended in 40 ml of dimethylsulfoxide and heated at from 74 to 75° C. for 30 minutes. 40 ml of tetrahydrofuran was added to the resulting solution and cooled to 0° C. To this was dropwise added a solution of 15.47 g (90.5 wt. %, 32.14 mmol) of N,N-dibenzyl-(L)-phenylalanine benzyl ester as dissolved in 20 ml of tetrahydrofuran, while keeping it at 0° C. After these were reacted at 0° C. for 30 minutes, 120 ml of an aqueous solution of 10% citric acid and 100 ml of ethyl acetate were added to the reaction mixture, which was thus subjected to phase separation. The aqueous layer thus separated was extracted once with 50 ml of ethyl acetate, and the resulting extract was combined with the previously-separated organic layer and then washed with 60 ml of a saturated saline solution. This was dried with anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=from 2/1 to 1/3) and then crystallized in toluene/hexane to obtain 11.16 g of the above-entitled compound. The yield was 85.6%. The integral ratio in 1H-NMR of the compound verified that the ratio of the diastereomers constituting it is about 1:1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]5[O:46][CH2:45][N:33]6[C:34]7[CH:35]=[CH:36][CH:37]=[C:38]([C:41]([O:43]C)=[O:42])[C:39]=7[CH:40]=[C:32]6[C:31]=5[N:47]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.O[Li].O.Cl>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]5[O:46][CH2:45][N:33]6[C:34]7[CH:35]=[CH:36][CH:37]=[C:38]([C:41]([OH:43])=[O:42])[C:39]=7[CH:40]=[C:32]6[C:31]=5[N:47]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(C(=O)OC)cccc5n3CO4)cc12
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(C(=O)O)cccc5n3CO4)cc12
Yield: 78 %

Procedure:
To a solution of methyl 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carboxylate (160 mg, 0.24 mmol) in dioxane (2 mL) and water (2 mL), LiOH.H2O (30 mg, 0.71 mmol) was added and the mixture was heated to reflux for 2 hours. Then removed dioxane and the mixture was diluted with water, adjusted to pH=3˜4 by 1 N HCl, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using PTLC (dichloromethane:MeOH=20:1) to provide 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carboxylic acid (120 mg, yield: 76%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.97˜8.02 (m, 2H), 7.86˜7.91 (m, 3H), 7.81 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (s, 2H), 7.31˜7.36 (m, 1H), 7.24˜7.29 (m, 2H), 6.14 (s, 2H), 3.35 (s, 3H), 2.96 (s, 3H), 2.88 (s, 3H). MS (M+H)+: 641.
Reaction SMILES: CCN(CC)CC.[C:8](Cl)(=[O:10])[CH3:9].[CH3:12][O:13][C:14]([C:16]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:31][NH:30][CH2:29]2)[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:29][N:30]([C:8](=[O:10])[CH3:9])[CH2:31]2)[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1)=[O:15]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(OC2CNC2)c2c(c1)OC(C)(C)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC2CN(C(C)=O)C2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Et3N (400 uL, 2.87 mmol) and acetyl chloride (70 uL, 0.99 mmol) were added to a solution of 4-(azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193c) (300 mg, 0.96 mmol) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 4 hr, then quenched with 1 N aqueous HCl (80 mL), and extracted with CH2Cl2 (80 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 80% EtOAc in hexanes to give a colorless oil (239 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.12 (br. s., 1 H) 6.76 (br. s., 1 H) 5.03 (br. s., 1 H) 4.55 (br. s., 1 H) 4.43 (br. s., 1 H) 4.03-4.19 (m, 2 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.92 (s, 3 H) 1.51 (br. s., 6 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:19](=[O:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1ccccc1C(F)(F)F
Yield: 42.8 %

Procedure:
Using the procedure of Step A of Example 6, 40.28 g of o-trifluoromethyl aniline and 42.5 g of phenylacetyl chloride were reacted in the presence of 27.83 g of triethylamine in 400 ml of benzene to obtain 29.85 g of N-(2-trifluoromethylphenyl)-benzeneacetamide melting at 104° C after crystallization from hexane which was used as is for the next step.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9](OCC)=O)[C:4]([O:6]CC)=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:23])=[C:19]([CH:22]=1)CCl.[OH-].[K+].O=S(Cl)[Cl:28]>C(O)C.O>[Br:14][C:15]1[CH:22]=[CH:19][C:18]([CH3:23])=[C:17]([CH2:9][CH:3]([CH3:2])[C:4]([Cl:28])=[O:6])[CH:16]=1
Reactant: Cc1ccc(Br)cc1CCl
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Br)cc1CC(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
In a three-necked round-bottom flask 9.50 g (0.413 mol) of sodium metal was dissolved in 260 ml of dry ethanol. To the resulting solution 72.0 g (0.413 mol) of diethyl methylmalonate was added. This mixture was stirred for 15 min, then 5-bromo-2-methylbenzyl chloride prepared above was added by vigorous stirring at such a rate as to maintain gentle reflux. This mixture was refluxed for an additional 2 h and then cooled to room temperature. A solution of 85 g of KOH in 250 ml of water was added. The resulting mixture was refluxed for 4 h to saponificate the ester formed. Ethanol and water were distilled off until temperature reached 95° C., and 1000 ml of water and then 12 M HCl (to pH 1) were added to the residue. The precipitated substituted methylmalonic acid was filtered off, washed with 3×100 ml of water, and then decarboxylated at 180° C. to give 3-(5-bromo-2-methylphenyl)-2-methylpropanoic. A mixture of this acid and 105 ml of SOCl2 was stirred at room temperature for 24 hours. After evaporation of an excess of thionyl chloride, the residue was distilled in vacuum to give 85.3 g (75% from 5-bromo-2-methylbenzaldehyde) 3-(5-bromo-2-methylphenyl)-2-methylpropanoyl chloride, b.p. 115° C./1 mm Hg.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH2:14][CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1.O>[ClH:19].[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH2:14][CH2:15][Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1nccn1Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: Cl
Product: ClCCCc1nccn1Cc1ccccc1

Procedure:
A solution of 1-benzyl-2-(2-carbethoxyethyl)imidazole (5.2 g) in dry ether (150 ml) is added, dropwise, to a stirred suspension of aluminium lithium hydride (1.0 g) in dry ether (150 ml) at gentle reflux. The suspension is subsequently heated under reflux for two hours, and then cooled during the successive addition of water (1 ml), 15% sodium hydroxide (1 ml) and water (3 ml). After heating under reflux for 0.5 hour and filtration, the insoluble solid is extracted with hot methanol (3 × 100 ml). The combined organic extracts are concentrated under reduced pressure and the residue dissolved in 2N hydrochloric acid. Following extraction with chloroform, the solution is basified with solid potassium carbonate. Chloroform extracts of the basic solution are dried over sodium sulphate and concentrated under reduced pressure, affording 1-benzyl-2-(3-hydroxypropyl) imidazole as a colourless viscous liquid (4.6 g). The carbinol (4.4 g) is dissolved in benzene (40 ml) and added to thionyl chloride (20 ml) at reflux temperature. After complete addition, water (four drops) is added and the mixture is heated under reflux for 0.5 hour. Concentration followed by the addition of cyclohexane yields a yellow solid. Recrystallization from ethanol-ether yields 1-benzyl-2-(3-chloropropyl)imidazole hydrochloride, m.p. 162°-164° C.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:18])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17].[OH-].[K+]>CCOCC>[CH3:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[O:18][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(O)c1C
Reactant: CC(C)(C)N1CC(O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C
Temperature: 155 °C

Procedure:
To a mixture of 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 6.7 parts of 2,3-xylenol 0.2 part of potassium hydroxide was added, and the mixture was heated at 155° C. for 20 hours. The reaction mixture was cooled and then dissolved in 100 parts of ether. The solution was washed three times with 50 parts of 2N-sodium hydroxide aqueous solution and extracted three times with 2N-hydrochloric acid aqueous solution. The extract was washed with 50 parts of ether and was made alkaline by adding 2N-sodium hydroxide solution gradually thereto. Then, the ether extraction was conducted three times and the extract was condensed and allowed to stand in a cool place. As a result crystals were formed, which were recrystallized twice from ether to yield 8.3 parts of 1-(2',3'-dimethylphenyloxy)-3-(tert.-butylamino)-2-propanol having a melting point of 57° C. Results of infra-red spectrum analysis and ultraviolet ray absorption analysis of the product are as follows:
Reaction SMILES: C[Mg]Br.[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].Br[CH2:14][C:15]#[C:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:14][C:15]#[C:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C#CCCCCCCCl
Reactant: CCCCCC(C)=CCC#CCBr
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(C)=CCC#CCC#CCCCCCCCl
Temperature: 25 °C

Procedure:
To 21 ml. of 3M ethereal methyl magnesium bromide in 47.5 ml. of dry tetrahydrofuran under nitrogen was added 9.2 g. of 1-chloro-7-octyne in 15 ml. of tetrahydrofuran. The mixture was heated under reflux for 30 min., then was allowed to cool to room temperature during another 30 minutes after which 365 mg. of cuprous chloride was added. The mixture was heated under reflux for 20 min., then a solution of 14 g. of 1-bromo-6-methyl-undec-2-yn-5-ene in 12.9 ml. of tetrahydrofuran was added. The mixture was heated under reflux for 10 hrs. then cooled in an ice bath and 250 ml. saturated aqueous ammonium chloride was added. Ether was added and the mixture was filtered through Celite (diatomaceous earth filter ald) and separated. The thus obtained ether layer was washed with saturated aqueous sodium chloride, dried with magnesium sulfate, and evaporated. The thus obtained residue was distilled through a rocking short-path distillation apparatus, collecting 11.5 g. of a mixture comprising 1-chloro-14-methylnonadeca-7,10-dlyn-13-ene at a bath temperature of 180°-190°/0.005 mm.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24]SCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5].[C:28](OCC)(=O)C.C(O)C>>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[CH:19]=[N:20][CH:25]=[CH:24][CH:28]=2)=[C:12]([NH2:26])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Product: COC(=O)CCNC(=O)c1ccc(NCc2cccnc2)c(N)c1

Procedure:
The same procedure is used as in (2). Rf value: 0.07 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [H-].[Na+].ICCO[CH:7]([O:9][CH2:10][CH2:11][I:12])[CH3:8].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]>O1CCCC1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])([CH2:20][CH2:19][O:18][CH2:8][CH2:7][O:9][CH2:10][CH2:11][I:12])[CH2:15][CH2:16][O:17][CH2:8][CH2:7][O:9][CH2:10][CH2:11][I:12])[CH3:20]
Reactant: CC(OCCI)OCCI
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)(CCOCCOCCI)CCOCCOCCI
Temperature: 25 °C
Yield: 95.7 %

Procedure:
1.71 g (0.036 mol) of sodium hydride was added to 40 ml of tetrahydrofuran dried with metallic sodium, and to this solution was added dropwise a mixed solution of 17.6 g (0.048 mol) of bis(2-iodoethoxy)ethane and 1.35 g (0.012 mol) of ethyl cyanoacetate, followed by 5-hours reflux under heating. Tetrahydrofuran was distilled off and the residue was cooled to room temperature, added with 1N hydrochloric acid until the litmus paper came to show acidity and then extracted three times with 50 ml of ether. After drying the extract over anhydrous sodium sulfate, ether was distilled off and the oily residue was passed through a basic alumina (activity II)-packed column and eluted with petroleum ether-ether (2:1) to obtain 3.43 g of 2,2-bis(8-iodo-3,6-dioxaoctyl)cyanoacetic acid ethyl ester, ##STR33## (yield: 48%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[Li][CH2:10]CCC.CI>C1COCC1>[CH3:10][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:1][C:2]1=[O:8]
Reactant: [Li]CCCC
Reactant: O=C1CCCCCN1
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCCCNC1=O
Reaction time: 2 h

Procedure:
To a solution of azepan-2-one (0.5 g, 4.42 mmol, 1 equiv) in anhydrous THF (20 mL) under nitrogen, was added n-BuLi (4.4 mL, 2.5 M in n-hexane, 11.06 mmol) dropwise at 0° C. The reaction mixture was kept at 0° C. for 2 h, then MeI (0.3 mL, 4.86 mmol) was added. After stirring for 1 h, the mixture was quenched with water and extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the crude product was directly used for the next step without further purification. MS (ESI): 128 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[H][H]>[Pd].C(O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[N:4][CH:5]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc(N)cn1
Yield: 49 %

Procedure:
2-Dimethylamino-5-nitropyridine (D34) (1.64 g, 9.8 mM) was stirred with 10% palladium on charcoal (0.16 g) in ethanol (200 ml) under 1 atmos. of hydrogen. After 6 h the catalyst was filtered off onto Kieselguhr and the filtrate was evaporated. The residue was dissolved in diethyl ether, filtered again, and chromatographed on silica gel (50 g) using ether as eluant. The eluted product was purified further by extraction with petrol (bp 60°-80° C.) to give the title compound as a reddish oil (0.66 g; 49%).