Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][C:6]2([CH3:14])[CH3:13].S(=O)(=O)(O)O.[N-:20]=[N+]=[N-].[Na+]>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:20][CH2:7][C:6]2([CH3:14])[CH3:13]
Reactant: COc1ccc2c(c1)C(C)(C)CC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)CNC2=O
Temperature: 60 °C
Yield: 98 %

Procedure:
A solution of 5-methoxy-3,3-dimethyl-indane-1-one (Intermediate 16, 3.3 g, 17.4 mmol) in benzene (50 mL) was treated with concentrated sulfuric acid (10 mL) and heated to 60° C. Sodium azide (1.95 g, 30 mmol) was added in small portions and after the addition was complete, the reaction mixture was heated further for 4 h. It was then cooled, diluted with water and extracted with chloroform (×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown solid (3.5 g, quantitative by weight).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH:18]3[CH2:20][CH2:19]3)[CH:16]=[N:17][C:13]=2[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH:18]3[CH2:20][CH2:19]3)[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Clc1cc2ncn(C3CC3)c2c(OCc2ccccc2)n1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3ncn(C4CC4)c3c(OCc3ccccc3)n2)cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4-(benzyloxy)-6-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridine 2.35 (306 mg, 1.02 mmol), 3,4-dimethoxyphenylboronic acid (297 mg, 1.63 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (36 mg, 0.051 mmol) and K2CO3 (450 mg, 3.3 mmol) were taken up in toluene (8.3 mL) and water (1.7 mL) under Ar. The stirred mixture was heated to 90° C. After 4 h, the temperature was increased to 100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.Br.[Br:24][C:25]1[CH:26]=[C:27]([CH2:32]Br)[C:28]([NH2:31])=[N:29][CH:30]=1.O>CN(C=O)C.C(OCC)(=O)C>[NH2:31][C:28]1[C:27]([CH2:32][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:26][C:25]([Br:24])=[CH:30][N:29]=1
Reactant: COC(=O)CNCc1ccc(OC)cc1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CN(Cc1ccc(OC)cc1)Cc1cc(Br)cnc1N
Reaction time: 8 h

Procedure:
Methyl 2-(4-methoxybenzylamino)acetate (760 mg, 3.63 mmol) and triethylamine (840 μL, 6.60 mmol) were successively added to a solution of 5-bromo-3-(bromomethyl)pyridine-2-amine hydrobromide (1.0 g, 3.30 mmol) in DMF (17 mL) at room temperature. The reaction mixture was stirred for 8 hours then diluted by addition of water (50 mL) and ethyl acetate (50 mL). The aqueous phase was separated and extracted with ethyl actetate (3×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulphate, filtered and concentrated to dryness. The title compound was obtained as an orange oil (1.05 g, 93%) which was used in the next step without further purification.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15].[NH2:27][C@H:28]([C:36]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([NH:27][C@H:28]([C:36]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:19])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
4.04 g (22.1 mmol) of EDCl was added to 60 ml of THF solution of 2.99 g (14.7 mmol) of Boc-Aib-OH (manufactured by Sigma-Aldrich Corporation), and 3.53 g (14.7 mmol) of H-Phe-NHPh obtained in Synthesis Example 6-2, followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 5.79 g of the product with a yield of 92.6%.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]3[N:18]=[N:17][NH:16][N:15]=3)=[CH:12][C:11]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:10]([Cl:23])[CH:9]=2)[S:4][CH:5]=1.[C:24]([O:30][CH2:31]Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[C:25]([C:24]([O:30][CH2:31][N:15]1[C:14]([C:13]2[C:8]([NH:7][CH2:6][C:3]3[S:4][CH:5]=[CH:1][CH:2]=3)=[CH:9][C:10]([Cl:23])=[C:11]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:12]=2)=[N:18][N:17]=[N:16]1)=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: NS(=O)(=O)c1cc(-c2nn[nH]n2)c(NCc2cccs2)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCn1nnnc1-c1cc(S(N)(=O)=O)c(Cl)cc1NCc1cccs1

Procedure:
In a similar manner to Example 12, azosemide can be reacted with chloromethyl pivalate, triethylamine and sodium iodide in DMF to yield 5-[1-(t-Butylcarbonyloxymethyl)-1H-tetrazol-5-yl]-2-chloro-4-[(2-thienylmethyl)amino]benzenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17]C)=[O:15])[CH2:7][CH2:8][CH3:9])=[C:4]([CH:21]=O)[CH:3]=1.CO.C[O-].[Na+].Cl>COC(=O)OC.O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:21][C:4]=2[CH:3]=1
Reactant: CCCN(CCCCC(=O)OCC)c1ccc(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COC(=O)OC
Solvent: O
Product: CCCN1CCCC(C(=O)OC)=Cc2cc(Br)ccc21
Temperature: 50 °C
Yield: 76.6 %

Procedure:
To a solution of ethyl 5-(4-bromo-2-formyl-N-propylanilino)pentanoate (5.0 g) in dimethylcarbonate (100 ml) was added a methanol solution of 28% sodium methoxide (3.5 g), and the mixture was heated at 50° C. for 2 hours under a nitrogen atmosphere. After cooling to 0° C. and neutralization with 1N hydrochloric acid, to the solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain yellow oil of methyl 8-bromo-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (3.5 g).
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])[OH:4].C(N(CC)CC)C.[OH:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[CH:27]=[CH:28][C:29](O)=[O:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C=O)C>[CH3:5][C:3]([O:4][C:29](=[O:30])[CH:28]=[CH:27][C:21]1[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=1[OH:19])([CH:2]=[CH2:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: O=C(O)C=Cc1ccc(O)cc1O
Reactant: C=CC(C)(O)CCC=C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CC(C)(CCC=C(C)C)OC(=O)C=Cc1ccc(O)cc1O
Reaction time: 1 h

Procedure:
To a solution of linalool (1.74 g, 11.3 mmol) and triethylamine (2.30 g, 22.6 mmol) in anhydrous THF (150 mL) stirred for 5 min at 22° C. is added 3-(2,4-dihydroxyphenyl)-acrylic acid (2.04 g, 11.3 mmol). To this heterogeneous solution is added BOP Reagent (5.00 g, 11.3 mmol; Aldrich #22,608-4) in DMF (10 mL), and the subsequent homogeneous reaction mixture is stirred for 1 h. The reaction mixture is partitioned between ether (200 mL) and water (400 mL); the organic layer is removed and washed with ether (200 mL). The combined organic layers are washed sequentially with saturated sodium bicarbonate solution (200 mL) and brine (200 mL). The organic layer is dried over anhydrous magnesium sulfate, vacuum filtered and concentrated to give 3-(2,4-dihydroxyphenyl)-acrylic acid 1,5-dimethyl-1-vinyl-hex-4-enyl ester as an oil that is purified by flash chromatography.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.[CH2:19]([N:21]([CH:30]([O:35][CH3:36])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20].CN(CCN(C)C)C.[CH3:45][Si:46](Cl)([CH3:48])[CH3:47]>C1COCC1>[CH2:19]([N:21]([CH:30]([O:35][CH3:36])[C:31]([CH3:32])([CH3:34])[CH3:33])[C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=1[Si:46]([CH3:48])([CH3:47])[CH3:45])[CH3:20]
Reactant: CCN(C(=O)c1ccccc1)C(OC)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN(C(=O)c1ccccc1[Si](C)(C)C)C(OC)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (140.6 mL, 182.8 mmol) was added dropwise to a dry-ice/acetone cooled solution of N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)benzamide (35 g, 140.6 mmol) and TMEDA (25.44 mL, 168.6 mmol) in THF (280 mL), maintaining the internal reaction temperature ≤-60° C. The yellow solution was stirred at -78° C. for 1 h, then was cannulated into a dry-ice/acetone cooled solution of TMSCl (26.72 mL, 210.6 mmol) in THF (140 mL) at a rate which maintained the internal reaction temperature ≤-55° C. The resulting mixture was warmed to 0° C. and partitioned between ether and sat aq NaHCO3. The ether solution was dried (MgSO4), concentrated, and kugelrohr distilled under vacuum to give 44.8 g of the title compound as a pale yellow solid, a 99% yield. m.p. 76°-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.[I:18]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:18][C:8]1[CH:7]=[C:6]([C@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(OC)cc2)C1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](c2ccc(OC)c(I)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl trans-3-(4-methoxyphenyl)cyclopentanecarboxylate (Step B) 60 mg, 0.256 mmol) in MeOH (2 ml), under nitrogen at RT, was added silver sulfate (80 mg, 0.256 mmol) followed by iodine (65.0 mg, 0.256 mmol). The resulting mixture was stirred at room temperature for 1 hour, then, filtered solids washing with MeOH and concentrated filtrate. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the titled compound. 1H NMR (500 MHz, CDCl3): δ 7.63 (d, J=2.2 Hz, 1H); 7.15 (dd, J=8.4, 2.2 Hz, 1H); 6.75 (d, J=8.4 Hz, 1H); 3.85 (s, 3H); 3.70 (s, 3H); 3.12 (m, 1H); 3.00 (m, 1H); 2.33 (ddd, J=13.2, 8.0, 4.6 Hz, 1H); 2.17-2.10 (m, 2H); 1.94 (m, 1H); 1.83 (m, 1H); 1.61 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16]>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([O:16][CH2:15][C:14]([CH3:19])([CH3:13])[CH2:17][OH:18])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: CC(C)(CO)CO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Product: CC(C)(CO)COc1ccc(N)cc1C#N
Yield: 59.7 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 2 using 2-chloro-5-nitrobenzonitrile (10 g) and 2,2-dimethyl-1,3-propanediol (5.7 g), the title compound (7.2 g) was obtained. melting point: 194-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[Na+].[Na+].O>CN1C(=O)N(C)CCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:10][NH:11][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: CCOCC
Product: CCOC(=O)CCCNC[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (1R)-N1 -(tert-butoxycarbonyl)-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (1.00 g) in N,N'-dimethylpropyleneurea (10 ml) were added successively ethyl 4-bromobutyrate (0.49 ml) and sodium carbonate (0.73 g) at room temperature in a stream of nitrogen. The mixture was stirred at the same temperature for 45 minutes and then at 110° C. for 3 hours. After cooling to room temperature, water (100 ml) and diethyl ether (50 ml) were added into the mixture. The organic layer was separated and washed with brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel (35 g) eluting with a mixture of dichloromethane-methanol (from 0% to 6% gradient solution) to give (1R)-N1 -(tert-butoxycarbonyl)-N2 -[3-(ethoxycarbonyl)-propyl]-1-(1H-indol-3-ylmethyl)-1,2-ethanediamine (0.78 g) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH2:35][C:36]#[N:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH2:35][C:36]#[N:37])[C:23](=[O:25])[CH2:22][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#CCCNCc1ccccc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(CCC#N)Cc2ccccc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-benzylamino-propionitrile
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:38][C:39]1[CH:43]=[CH:42][S:41][CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: ClCc1ccsc1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccsc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 36 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.37 g) and 3-(chloromethyl)thiophene (0.21 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained. By the reaction and treatment of this compound (0.11 g), in the same manner as in Example 133, 5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.054 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:11]=3[S:12][C:3]=12.[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].Cl.N1C=CC=CC=1>CS(C)=O.C(Cl)(Cl)Cl>[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:11]=3[S:12][C:3]=12
Reactant: N#Cc1cnc2c(sc3c([N+](=O)[O-])cccc32)c1Cl
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cnc2c(sc3c([N+](=O)[O-])cccc32)c1Nc1cccc(Br)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
A mixture of 4-chloro-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile (0.27 g, 0.9 mmol), 3-bromoaniline (3.16 g, 18.4 mmol), and pyridine hydrochloride (0.06 g) in 15 mL of DMSO is stirred in the microwave (PROLABO unit) at 140° C., power range 0-10%, for one hour. The final reaction mixture is cooled, dissolved in 100 mL of chloroform, washed with 2N HCl (2×50 mL), then with saturated aqueous sodium bicarbonate (50 mL), and dried over sodium sulfate. The solvent is evaporated, and the desired compound purified by silica gel chromatography, eluting with 9:1 chloroform/methanol. After washing with diethyl ether and ethyl acetate, 4-(3-bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile (0.215 g, 55%) is obtained as a yellow solid, m. p. 288-290° C.
Reaction SMILES: NC1C([N+:8]([O-:10])=[O:9])=CC=CC=1C.[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13].[N+]([O-])(O)=O>C(OC(=O)C)(=O)C>[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:8]([O-:10])=[O:9])[CH:15]=1)[CH3:13]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: CCc1ccc(N)cc1
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 69.32 %

Procedure:
According to the method of synthesis for 2-amino-3-nitrotoluene (Organic Syntheses Collective Volume IV P.42-45) 6 g of 4- ethylaniline was added dropwise to 30 ml of acetic anhydride and then, the mixture was treated dropwise with 6.3 ml (100 m mol) of 70% nitric acid at 12°-13° C. After the mixture was stirred for some time at 10°-12° C., the reaction solution was poured into an ice water. Oily product was separated and heated with 15 ml of concentrated hydrochloric for one hour. The reaction solution was alkaline with dilute aqueous sodium hydroxide and then, partitioned with 100 ml of chloroform. The organic layer was washed with water and dried on anhydrous sodium sulfate. Removal of the solvent in vacuo gave 5.76 g (69.32%) of 4-ethyl-2-nitroaniline.
Reaction SMILES: [C:1]1([OH:7])C=CC=C[CH:2]=1.CC(C)N=C=NC(C)C.FF.[CH3:19][O:20][CH2:21][CH:22]([OH:24])[CH3:23]>>[C:1]([O:24][CH:22]([CH3:23])[CH2:21][O:20][CH3:19])(=[O:7])[CH3:2]
Reactant: Oc1ccccc1
Reactant: COCC(C)O
Agent: CC(C)N=C=NC(C)C
Agent: FF
Product: COCC(C)OC(C)=O

Procedure:
To 1.0 g of a commercially available phenol novolac resin (manufactured by Gunei Chemical Industry Co., Ltd.), 0.2 g of an epoxy-based cross-linking agent (manufactured by Tohto Kasei Co., Ltd., trade name: YH434L) and 0.003 g of a surfactant (manufactured by DIC Corporation, product name: MEGAFAC [registered trademark] R-30, composed of a fluorine-based surfactant) were added. The resultant mixture was dissolved in 6.7 g of propylene glycol monomethyl ether and 15.6 g of propylene glycol monomethyl ether acetate to obtain a solution. Subsequently, the solution was filtered using a polyethylene microfilter with a pore diameter of 0.2 μm to prepare a solution of the organic underlayer film forming composition for use in a lithography process with a multilayer film.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17]CC)=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([N:28]1CCCC(C(Cl)=O)C1)(=O)[C:21]1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl.C(N)C>>[CH2:20]([NH:28][C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10]1)=[O:17])[CH3:21]
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Agent: CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C1CCCN(C(=O)c2ccccc2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with 1-benzoyl-3-piperidinecarbonyl chloride (216.2 mg; 0.86 mmol), diisopropylethylamine (350 μl; 2.0 mmol) and commercially available ethylamine hydrochloride (74.6 mg; 0.86 mmol). The crude product was purified by chromatography on silica, eluting with 100% ethyl acetate, giving N-ethyl 1-benzoyl-3-piperidinecarboxamide (144.3 mg) as a white, sticky, semi-solid. MS m/z (positive ion) 362 (25), 261 (MH+; 100).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.Cl>O1CCCC1>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][C:10]([CH3:18])([CH3:9])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:22][CH:21]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)C(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
At −78° C., 34.7 ml (69.4 mmol) of a 2 M lithium diisopropylamide solution are slowly added dropwise to a solution of 10.0 g (69.34 mmol) of tert-butyl 2-methylpropionate (Example I-1) in 100 ml of tetrahydrofuran. After the addition has ended, the mixture is stirred at −78° C. for 1 h, and a solution of 15.76 g (63.04 mmol) of 4-bromobenzyl bromide in 10 ml of tetrahydrofuran is then added and the mixture is stirred at −78° C. for 1 h. The reaction is then warmed to room temperature and poured into 100 ml of 1 N hydrochloric acid, the phases are separated and the aqueous phase is extracted 3× with diethyl ether. The combined organic phases are washed with NaHCO3 solution, dried over sodium sulphate and freed from the solvent under reduced pressure. Distillative purification of the residue under oil pump vacuum gives 16.75 g (85%) of tert-butyl 3-(4-bromophenyl)-2,2-dimethylpropionate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@@H:26]([C@@H:28]2[CH2:32][O:31]C(C)(C)[O:29]2)[CH3:27])[N:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@H:26]([CH3:27])[C@@H:28]([OH:29])[CH2:32][OH:31])[N:12]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step (0.13 g) in DCM (5 mL) was added iron (III) chloride hexahydrate (0.24 g). The reaction mixture was stirred at ambient temperature for 1 h, then saturated aqueous sodium bicarbonate (10 mL) was added. The layers were separated and the aqueous material extracted with DCM (3×10 mL) and EtOAc (3×10 mL). The combined organic extracts were washed with saturated sodium chloride, dried (MgSO4), filtered and evaporated. The residual pale yellow solid was slowly precipitated from DCM, filtered and the resulting material washed with minimal cold DCM (2×1 mL) to afford the title compound as a white powder. Yield: 45 mg.