Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[C:46]([CH3:47])=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:58])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ncccc4C)cc2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4c(C)ccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-N-[4-[hydroxy(3-methylpyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (291 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 128 mg) at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9) and further recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 100) (210.9 mg) as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CN(C=O)C>[O:13]=[C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11][N:10]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCCN1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of 1-benzylimidazolidin-2-one (3.5 g, 19.9 mmol) in DMF (50 ml) at 0° C. were added lithium tert-butoxide (1.9 g, 23.8 mmol) and tert-butyl bromoacetate (3.2 ml, 21.8 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue was washed with n-hexane, and dried to give tert-butyl 2-(2-oxo-3-benzylimidazolidinyl)acetate (5.08 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:14]2[N:15]=[N:16][NH:17][N:18]=2)[CH2:10][C@H:9]1[CH2:34][CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:38](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([C:30]([F:32])([F:33])[F:31])[CH:21]=2)[C:14]2[N:15]=[N:16][N:17]([CH3:38])[N:18]=2)[CH2:10][C@H:9]1[CH2:34][CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)CN1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CN1C(=O)OC(C)(C)C
Yield: 86.1 %

Procedure:
A solution of the crude (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (52 mg, 0.10 mmol), methyl iodide (90 mg, 0.51 mmol) and potassium carbonate (28 mg, 0.20 mmol) in DMF (1.3 mL) is stirred at 50° C. for 2 hours. The reaction mixture is quenched with saturated ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (45 mg, 44% overall yield in 4 steps).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.[C:13]([OH:16])#[C:14][CH3:15]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:15][C:14]#[C:13][OH:16])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CC#CO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CC#CO)cc1
Temperature: 65 °C
Yield: 27.4 %

Procedure:
4-Bromophenylacetic acid methyl ester (23 g, 0.1 mol) was dissolved in dry triethylamine (80 ml) with propynol (5.82 ml, 0.1 mol). After the addition of cuprous iodide (0.3 g) and bis (triphenylphosphine)palladium (II) chloride (1 g) the reaction mixture was heated at 65° C. under nitrogen for 14 h. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate (500 ml) and washed successively with 0.5M citric acid solution (2×200 ml), saturated sodium hydrogen carbonate solution (2×200 ml) and brine (1×150 ml). The organic solution was dried (Na2SO4), filtered and concentrated in vacuo to give an oil which was purified by chromatography on silica gel using 20% ethyl acetate in hexane as eluent to give the required compound (5.6 g) as an oil. δ (360 MHz, CDCl3) 3.62 (2H, s, CH2CO2CH3), 3.69 (3H, s, CH2CO2CH3), 4.48 (1H, s, HOCH2), 7.22 (2H, d, J=8.2 Hz, ArH), 7.39 (2H, d, J=8.2 Hz, ArH); m/e 204 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:31][CH3:32])=[C:9]([S:11]([C:14]2[CH:15]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=[C:18]([O:20]C(C)(C)C)[CH:19]=2)(=[O:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:31][CH3:32])=[C:9]([S:11]([C:14]2[CH:15]=[C:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:17]=[C:18]([OH:20])[CH:19]=2)(=[O:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cc(OC(C)(C)C)cc(-c3ccccc3)c2)c(SC)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(S(=O)(=O)c2cc(O)cc(-c3ccccc3)c2)c(SC)s1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
4-(5-tert-butoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (55 mg, 0.11 mmol) was dissolved in 1:1 TFA/DCM (10 mL) and stirring for 1 h. Removal of the solvent in vacuo yielded the title compound (48 mg, 98%), which was used without further purification.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>C1(C)C(C)=CC=CC=1>[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1OCCCl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)Oc1ccccc1OCCCl
Temperature: 140 °C

Procedure:
3.4 g (0.024 mol) of chlorosulfonyl isocyanate are added dropwise at 25° C. to a solution of 3.45 g (0.02 mol) of 2-(2-chloroethoxy)phenol in 20 ml of xylene. When the dropwise addition is complete, the temperature is increased slowly to 140° C., and the mixture is refluxed for 2 hours. The mixture is cooled and the solvent as well as excess chlorosulfonyl isocyanate are removed on a rotary evaporator. The yellow oil which remains (5.6 g=100% of theory) is employed without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)([C:17](=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].C(N(C(C)C)CC)(C)C>ClCCCl>[CH:19]1([NH:18][C:17]([C:14]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:41](=[O:43])[CH3:42])=[CH:29][CH:28]=3)[CH2:13][CH2:12][N:11]([C:9](=[O:10])[C@@H:8]([NH2:7])[CH2:34][C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH2:16][CH2:15]2)=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc(N)cc2)(C(=O)NC2CCCCC2)CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {2-[4-(4-aminobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (0.352 mmol; 0.2 g) in 1,2-dichloroethane (5 mL) was added acetic anhydride (0.422 mmol; 0.043 g) and N,N-diisopropyl-N-ethylamine (0.703 mmol; 0.123 mL) and the resulting solution was stirred for 3 hours at room temperature. The resulting mixture was then evaporated and the residue was purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in tetrahydrofuran (10 mL) and a 4N HCl in 1,4-dioxane solution (15 mL), and the mixture was then stirred for 6 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 4-(4-acetylaminobenzyl)-1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-piperidine-4-carboxylic acid cyclohexylamide as a hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl.C(O)C.O.O.[Sn](Cl)Cl>>[CH2:13]([CH:9]1[NH:8][C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:15][C:10]1=[O:11])[CH3:14]
Reactant: CCC(Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCC1Nc2ccc(F)cc2NC1=O
Temperature: 78 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
The heterogeneous mixture of 2-(4-fluoro-2-nitrophenylamino)butanoic acid (181.7 g, 750.0 mmol), 3 N aq. HCl (750.0 ml, 2250 mmol), and ethanol (1923 ml, 750.0 mmol) in 5-L three neck round bottom flask was added Tin(II) chloride dihydrate (507.7 g, 2250 mmol) and the organe mixture was heated at 78° C. with stirring using an overhead stirrer for 4 h ([Note 1]: The orange heterogeneous mixture became an orange homogeneous mixture and the orange color changed to a red color over ˜2 hour). After 4 h, the mixture was cooled to rt and concentrated under reduced pressure to remove ethanol, and left at rt for 48 h. The resulting yellow precipitate was collected by filtration and washed with water (500 mL). The yellow solid was suspended in ice water (1 L) and the mixture was adjusted ˜pH 13 with KOH (−250 g). The heterogeneous mixture was extracted with DCM (1 L×3). The combined organic layers were washed with water (1 L×1) and brine (1 L×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.92 g, 41.8% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (s, 1H), 6.68 (dd, J=8.6, 5.5 Hz, 1H), 6.47-6.61 (m, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.62 (ddd, J=6.7, 5.0, 2.0 Hz, 1H), 1.50-1.72 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), Mass Spectrum (ESI) m/e=195.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@@H:12]3[CH2:23][C@@H:15]4[CH2:16][N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:18][C@@H:14]4[C@H:13]3[CH3:24])=[C:9]([C:25]([NH2:27])=[O:26])[CH:8]=[N:7][N:6]2[CH:28]=1)#[N:2].[N:29]([Sn](CCCC)(CCCC)CCCC)=[N+:30]=[N-:31]>CN1CCCC1=O>[CH3:24][C@@H:13]1[C@@H:14]2[C@@H:15]([CH2:16][N:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:18]2)[CH2:23][C@H:12]1[NH:11][C:10]1[C:5]2[N:6]([CH:28]=[C:3]([C:1]3[N:29]=[N:30][NH:31][N:2]=3)[CH:4]=2)[N:7]=[CH:8][C:9]=1[C:25]([NH2:27])=[O:26]
Reactant: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(C#N)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CN1CCCC1=O
Product: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nn[nH]n3)cc12

Procedure:
A solution of 6-cyano-4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (34 mg, 0.084 mmol) and azidotributyltin (0.028 mL, 0.101 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated to 180° C. under microwave for 1 h. LCMS analysis showed that the expected product was observed as the major peak. The reaction mixture was taken to the next step without purification. MS (ES+) m/z: 446.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C=O.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:16])=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)[CH3:21]
Reactant: CNC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=O
Product: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Upon intermixing of 2,6-di-tert.butyl-4-methylphenol, formaldehyde and dimethylamine in an alcoholic medium at a temperature within the range of from 80° to 90° C. a condensation reaction occurs resulting in the formation of N,N-dimethyl-3,5-di-tert.butyl-4-hydroxybenzylamine. Along with the latter, formed are readily-volatile reaction products, i.e., water and bis-amine. In addition, alcohol is contained in the reaction mass. The thus-selected temperature range is optimal. When temperature is decreased below the lower limit, the reaction rate of condensation is substantially reduced. Upon increasing temperature above 90° C., decomposition of the Mannich base is observed.
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:24])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][NH2:17])[C@@H:11]([CH:19]([CH3:22])[CH2:20][CH3:21])[C:10]1=[O:23])(C)(C)C.Cl.[NH:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[C:27]([NH2:29])=[NH:28]>>[ClH:1].[NH:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:17][CH2:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][C:7]([OH:6])=[O:24])[C:10](=[O:23])[C@@H:11]2[CH:19]([CH3:22])[CH2:20][CH3:21])=[O:18])=[O:35])=[CH:32][CH:31]=1)[C:27]([NH2:29])=[NH:28]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CCC(C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)CN
Agent: Cl
Product: CCC(C)[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CNC(=O)c1ccc(NC(=N)N)cc1

Procedure:
(S)-4-Glycyl-3-(1-methylpropyl)-2-oxopiperazine-1-acetic acid t-butyl ester hydrochloride obtained in Working Example 64 (364 mg) and 215 mg of 4-guanidino benzoic acid hydrochloride were subjected to substantially the same procedure as in Working Example 39 to afford 190 mg of the title compound as colorless powder.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.Cl.[C:7]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH2:12])#[N:8]>>[C:7]([C:9]1[CH:10]=[C:11]([NH:12][NH2:1])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])#[N:8]
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1C#N
Agent: Cl
Agent: [Na+]
Product: COc1ccc(NN)cc1C#N
Yield: 69.1 %

Procedure:
To an aqueous solution (150 ml) of 3-cyano-4-methoxyaniline hydrochloride (72 g) were added sodium nitrite (29.7 g), stannous chloride dihydrate (266 g) and con. hydrochloric acid (437 ml) with stirring under ice-cooling. After the completion of the reaction, precipitated crystals were collected by filtration. The crystals were added to water, and the mixture was neutralized with aqueous sodium hydroxide solution, extracted with a mixed solvent of toluene and tert-butanol, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 44 g of 3-cyano-4-methoxyphenylhydrazine.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)CCBr
Reactant: Ic1ccnc2c[nH]nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)CCn1cc2nccc(I)c2n1
Temperature: 120 °C

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (342 mg, 1.396 mmol), 4-bromo-2-methylbutan-2-ol (233 mg, 1.396 mmol) and Cs2CO3 (455 mg, 1.396 mmol) were combined in DMF (5 mL) and heated in a microwave at 120° C. for 60 minutes. The reaction was cooled, filtered, and concentrated to give a residue which was purified by silica column eluted using a step gradient of EtOAc (0-90%) in hexanes to give 4-(7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylbutan-2-ol.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][C:9]([Br:13])=[C:10]([Br:12])[CH:11]=1)=[O:6])C.[OH-].[Na+].C(O)(=O)C>O>[Br:12][C:10]1[CH:11]=[C:7]([C:5](=[O:6])[C:4]([OH:14])=[O:3])[S:8][C:9]=1[Br:13]
Reactant: CCOC(=O)C(=O)c1cc(Br)c(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(=O)c1cc(Br)c(Br)s1
Yield: 86 %

Procedure:
(4,5-Dibromothiophen-2-yl)-oxo-acetic acid ethyl ester (1.00 g, 2.92 mmol) was stirred in a mixture of 5 ml water and 1 N NaOH (3.65 ml, 3.65 mmol) at room temperature for 2 hours. The reaction was then poured into 2 N acetic acid, and extracted into 100 ml ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated under vacuum to provide (4,5-dibromothiophen-2-yl)-oxo-acetic acid (788 mg, 86%). MS (M−H)−: 312.73; 1H NMR (300 MHz, DMSO-d6) δ7.98 (s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(Cl)cccc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccccc2)c1CBr
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A stirred solution of 3-chloro-2-methyl-[1,1'-biphenyl] (13.5 g, 0.067 mole) and N-bromosuccinimide (11.8 g, 0.067 mole) in 125 ml of carbon tetrachloride was irradiated and heated to reflux for 61/2 hours with a 250 watt brooder lamp. The light/heat source was turned off and the reaction mixture stirred at room temperature for approximately 64 hours. The reaction mixture was again irradiated and heated for two hours with the brooder lamp. The mixture was cooled, a solid precipitate filtered off, and the filter cake washed with two 50 ml portions of carbon tetrachloride. The filtrate was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 2-bromomethyl-3-chloro-[1,1'-biphenyl] as an oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=1)\[CH3:21])[CH3:16]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(Cl)c1
Temperature: 23 °C
Yield: 40.3 %

Procedure:
Potassium t-butoxide (7.40 g, 0.066 mol) was added to a stirred solution of 3-chloro-phenol (4.22 g, 0.033 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (3.20 g, 40%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1/[CH:11]=[CH:12]/[CH:13](O)[CH3:14].C1(C)C=CC(S(O)(=O)=[O:23])=CC=1.CCOCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8](=[O:23])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[CH:11]=[CH:12][CH:13]=[CH2:14]
Reactant: CC1=C(/C=C/C(C)O)C(C)(C)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CC=CC1=C(C)C(=O)CCC1(C)C
Yield: 2715 %

Procedure:
A solution of 70 g of crude 3-oxo-β-ionol and 1.5 g of paratoluenesulphonic acid in 300 ml of toluene is stirred at reflux temperature for 40 minutes with simultaneous removal of the water formed by means of a water separator. The cooled mixture is treated with 300 ml of ether, the organic phase is washed three times with soda solution and three times with water, dried and concentrated. There are obtained 61 g of crude product which contains more than 90% of 2,4,4-trimethyl-3-(buta-1,3-diethyl)cyclohex-2-en-1-one according to gas-chromatographical analysis. Distillation of the crude product over a 15 cm column gives 45 g of olfactorily-good 2,4,4-trimethyl-3-(buta-1,3-dienyl)cyclohex-2-en-1-one of boiling point 74°-75° C./0.06 mm Hg.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH:11]1([CH:17]([C:19]2[CH:20]=C(O)[CH:22]=[C:23]([CH:25]=2)[OH:24])[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:17]([C:19]2[CH:25]=[C:23]([OH:24])[C:22]3[C:2]4[CH2:6][CH2:5][S:4][C:3]=4[C:7](=[O:8])[O:9][C:10]=3[CH:20]=2)[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(c1cc(O)cc(O)c1)C1CCCCC1
Reactant: COC(=O)C1SCCC1=O
Product: CC(c1cc(O)c2c3c(c(=O)oc2c1)SCC3)C1CCCCC1

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(1-cyclohexylethyl) resorcinol to give 7-(1-cyclohexylethyl)-1,2-dihydro-9-hydroxy-4-oxo-4H-thieno[2,3-c] [1]benzopyran.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](O)[N:7]=1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1.O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(O)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(S)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 119.4 %

Procedure:
6-Hydroxy-pyridine-2-carboxylic acid ethyl ester (1.8 g, 10.7 mmol) was dissolved in THF (50 mL), and Lawesson's reagent (2.18 g, 5.35 mmol) was added thereto. The mixture was stirred at room temperature for 24 hours. After the termination of the reaction, the reactant was added with water and then extracted with DCM. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure and then separated by column chromatography to obtain the title compound (1.17 g, 59%).