Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]([C:27]2[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:28]=2)=[CH:25][C:24]([C:36]([F:39])([F:38])[F:37])=[N:23]1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[C:26]([C:27]2[S:31][C:30]([S:32]([N:12]3[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]3)(=[O:34])=[O:33])=[CH:29][CH:28]=2)=[CH:25][C:24]([C:36]([F:39])([F:37])[F:38])=[N:23]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN1CCN(S(=O)(=O)c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)s2)CC1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
Triethylamine (0.15 mL, 1.1 mmol) and a small amount of DMAP were dissolved in 1,2-dichloroethane (2 mL) in a reaction vial. This solution was treated with 1-methyl piperazine (50 μL, 0.45 mmol) followed by 5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonyl chloride (145 mg, 0.34 mmol) as a solution in 1,2-dichloroethane (1 mL). After stirring 4½ hours at ambient temperature the reaction was quenched by dilution with CH2Cl2 and water. Saturated NaHCO3 was added and the basic aqueous was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product as a pale yellow oil. This crude product was purified by flash column chromatography eluting with a gradient from CH2Cl2 to 16% acetonitrile/CH2Cl2 to afford 1-(5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-ylsulfonyl)-4-methylpiperazine (90.5 mg, 54% yield) as a brittle white foam. MS(ES): 491 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])[CH:18]=1
Reactant: O=c1[nH]ccc2ccc(C(F)(F)F)cc12
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=c1c2cc(C(F)(F)F)ccc2ccn1-c1cccnc1
Yield: 59.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-2H-isoquinolin-1-one (I-29d: 0.12 g, 0.56 mmol) was reacted with 3-bromo-pyridine (0.106 g, 0.6 mmol), DMSO (2 mL), copper iodide (0.021 g, 0.12 mmol), 8-hydroxy-quinoline (0.018 g, 0.12 mmol) and potassium carbonate (0.15 g, 1.1 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in DCM) afforded 96 mg of the product (70.58% yield).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:18][CH2:17][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9]1.Cl[C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][CH2:27][N:26]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[C:24]=2[N:25]=1.O>O1CCCC1>[CH2:15]([O:14][C:12]([CH:11]1[CH2:10][CH2:9][N:8]([C:20]2[N:21]=[CH:22][C:23]3[CH:29]=[CH:28][CH2:27][N:26]([NH:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]5[O:38][CH2:39][O:40][C:34]=5[CH:33]=4)[C:24]=3[N:25]=2)[CH2:18][CH2:17]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ncc2c(n1)N(NCc1ccc3c(c1)OCO3)CC=C2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ncc3c(n2)N(NCc2ccc4c(c2)OCO4)CC=C3)CC1
Yield: 99.8 %

Procedure:
41 mg of triethylamine and 190 mg of ethyl isonipecotate were added to a solution of 127 mg of 2-chloro-8-(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]pyrimidine in 8 ml of tetrahydrofuran. The obtained mixture was refluxed for 2 hours, followed by the addition of water. The resulting mixture was extracted with chloroform twice. The organic layers were combined, dried over magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica gel chromatography (with ethyl acetate) to give 175 mg of the title compound (in a yield of 100%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.[CH3:17][O:18][C:19]([C@H:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[N:22]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:20].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:22][C@H:21]([CH2:26][CH2:25][CH2:24][C:23]([C:15]1[C:10]([F:9])=[N:11][C:12]([F:16])=[CH:13][CH:14]=1)=[O:27])[C:19]([O:18][CH3:17])=[O:20])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(F)nc1F)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
LDA (1.5 M solution in THF, 3.2 mL) was added to a solution of 2,6-difluoropyridine (492 mg) in THF (25 mL) at −78° C., and the reaction solution was stirred at −78° C. for 2.5 hours. A solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS No. 183890-36-0, 1.0 g) in THF (5 mL) was added to the reaction solution at −78° C. The reaction solution was stirred at −78° C. for one hour and at 0° C. for 2.5 hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was heated to room temperature. Thereafter, the organic layer was separated, and the resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 148 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([O:41][CH3:42])[C:35]([O:43][CH3:44])=[N:34]2>O1CCOCC1.O>[CH3:42][O:41][C:36]1[C:35]([O:43][CH3:44])=[N:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([CH2:30][NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=3[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)=[O:13])[CH:32]=2)[N:37]=1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: COc1nc2ccc(CBr)cc2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C#CCOc1ccc(NCc2ccc3nc(OC)c(OC)nc3c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 82 mg (0.280 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 3 ml dioxane is added 193 mg (1.40 mmol) potassium carbonate and 119 mg (0.419 mmol) 6-Bromomethyl-2,3-dimethoxy-quinoxalin. The mixture is stirred at 80° C. for two days, diluted with water and extracted with CH2Cl2. Purification of the crude product by chromatography (ethyl acetate/hexanes 1:1) affords a yellow oil.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.C(OC([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCNCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with 1-tert-butoxycarbonyl piperazine in N,N-dimethylacetamide at room temperature followed by treatment with trifluoroacetic acid at room temperature to yield trans-N-methyl-N-[4-(4-piperazin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 504 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@@H:20]2[CH2:28][N:27]3[C@H:22]([CH2:23][O:24][CH2:25][CH2:26]3)[CH2:21]2)=[C:15]([N+:29]([O-])=O)[CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1.C1C=CC(O[C:58](OC2C=CC=CC=2)=[N:59][C:60]#[N:61])=CC=1>O1CCCC1.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[O:7][CH2:8][C:9]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@@H:20]3[CH2:28][N:27]4[C@H:22]([CH2:23][O:24][CH2:25][CH2:26]4)[CH2:21]3)/[C:58](=[N:59]/[C:60]#[N:61])/[NH:29][C:15]=2[CH:14]=1
Reactant: O=[N+]([O-])c1cc(/C=C2/c3ccc(F)cc3OCc3c(F)cccc32)ccc1N[C@H]1C[C@H]2COCCN2C1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#C/N=c1\[nH]c2cc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)ccc2n1[C@H]1C[C@H]2COCCN2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
Dissolve [4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7S,8aS)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (0.009 mol, 5.0 g) in tetrahydrofuran (40 mL). Add triethylamine (0.009 mol, 0.9 g) and 10% platinum on carbon (1.0 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 3 h. Filter off the catalyst through a plug of diatomaceous earth, add pyridine (40 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.35 g) to the filtrate. Stir at room temperature for 16 h, then heat at 60-70° C. for 8 h. Remove the solvent under reduced pressure. Dissolve the resulting residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify on a silica gel column using 1% methanol in dichloromethane as eluent to give the title compound (1.9 g, 36%). LC-MS m/z 526.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[F:11][C:6]1[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=[CH:2][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F

Procedure:
6-Chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.5 g, 1.69 mmol) was dissolved in methanol (15 mL), and Pearlman's catalyst (one weight equivalent, 0.5 g, 20% Pd(OH)2 on carbon, 50% by weight water) was added. This mixture was subjected to a balloon of hydrogen for 3 hours and then filtered through GF/F filter paper. The filtrate was concentrated to 2-fluoro-3-(propylsulfonamido)benzoic acid (396 mg, 90%) as a solid. MS (M-H+) 262. NMR (DMSO-d6, 400 MHz) δ 13.36 (s, 1H), 9.76 (s, 1H), 7.58-7.70 (m, 2H), 7.26 (t, 1H, J=8), 3.10 (t, 2H, J=8), 1.69-1.80 (m, 2H), 0.98 (t, 3H, J=8).
Reaction SMILES: [NH2:1][C:2]1[NH:3][N:4]=[CH:5][CH:6]=1.FC1C=CC(C(O[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=O)=CC=1>CCO.Cl.C(Cl)(Cl)Cl.CO>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:1]=[C:2]3[NH:3][N:4]=[CH:5][C:6]=23)=[CH:28][CH:27]=1
Reactant: Nc1ccn[nH]1
Reactant: O=C(OC(=Cc1ccncc1)c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Yield: 0.5 %

Procedure:
To a solution of 3-amino-2H-pyrazole (60 mg, 71.8 mmol) in EtOH (2 mL) and 1 drop of 37% HCl, 1-(4-fluorophenyl)-2-(4-pyridyl)vinyl 4-fluorobenzoate (0.22 g, 65.0 mmol, obtained in reference example 4) was added under argon atmosphere. This was heated to reflux for 3 days. The mixture was diluted with CHCl3 and MeOH. It was washed with saturated NaHCO3. The aqueous phase was extracted with CHCl3 (×2). The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 58 mg of the desired product in a solid white form (yield: 23%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[C:16]1([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[OH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:27]2[CH2:26][CH2:25][CH:24]([C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[OH:23])[CH2:29][CH2:28]2)=[O:14])=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added diphenyl(piperidin-4-yl)methanol (13.3 mg, 0.074 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C29H28N2O3: 452.2100, found 452.2107.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=N/S(C2SC=CC=2)(=O)=O)/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:38][S:35]([C:32]2[CH:31]=[CH:30][C:29]([CH3:28])=[CH:34][CH:33]=2)(=[O:37])=[O:36])[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CSC1=CC(=NS(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O

Procedure:
5.2.20 Ethyl 2-(1-oxo-4-(tosylimino)-1,4-dihydronaphthalen-2-ylthio)acetate (81) was prepared according to the procedure for 8a except using 4-methylbenzenesulfonamide, TiCl4.2THF and THF as solvent. The title compound 100.7 mg (46.9%) was obtained according to the workup procedure for 12a as a yellow solid, m.p.: ° C.
Reaction SMILES: N(C(OCCOC)=O)=NC(OCCOC)=O.[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[OH:28].[CH3:29][C:30]1([CH3:37])[C:32]([CH3:34])([CH3:33])[CH:31]1[CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[O:28][CH2:35][CH:31]1[C:32]([CH3:34])([CH3:33])[C:30]1([CH3:37])[CH3:29]
Reactant: CC1(C)C(CO)C1(C)C
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)cc1OCC1C(C)(C)C1(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
1.97 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.08 g of 2,5-dimethyl-4-nitrophenol, 0.83 g of (2,2,3,3-tetramethylcyclopropyl)methanol, 2.04 g of triphenylphosphine and 100 mL of toluene at 0° C., and the mixture was stirred at 90° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.15 g of 2,5-dimethyl-4-nitro-1-[(2,2,3,3-tetramethylcyclopropyl) methoxy]benzene.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][C:11]([SH:14])([CH3:13])[CH3:12].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:14][C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC(C)(C)C
Yield: 34.7 %

Procedure:
Ethyl 2-bromoisobutyrate (40.0 g, 0.205 mole), 2-methyl-2-propanethiol (20.4 g, 0.0226 mole), potassium hydroxide (14.4 g, 0.226 mole), ethyl alcohol (100 g) were combined and reaction mixture was refluxed for six hours prior to quenching. Crude yield: 61.0%; Distilled yield: 34.7%. Flavor description: astringent, tropical, mango, citrus, grapefruit, onion, catty, marigold, herbal, floral, geranium, green. Fragrance description: grapefruit, passion fruit, papaya, dandelion, marigold, caraway, berries, slight onion.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12]O.O=P(Cl)(Cl)[Cl:16]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][Cl:16]
Reactant: Cc1c(CCO)cccc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(CCCl)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitrophenyl ethyl alcohol (100 g) is added to toluene (500 ml). POCl3 (62 ml) is added to the reaction mixture and refluxed for 2 to 3 hrs. Toluene is distilled off completely to give 2-Methyl-3-nitro phenylethyl chloride
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][N:24]3[C:30](=[O:31])[CH2:29][C:28]4[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:27]=4[CH2:26][CH2:25]3)[CH2:18]2)=[CH:11][C:10]=1[O:40][CH3:41])C1C=CC=CC=1>C(O)(=O)C>[CH3:41][O:40][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][N:24]3[C:30](=[O:31])[CH2:29][C:28]4[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:27]=4[CH2:26][CH2:25]3)[CH2:18]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3ccc(OCc4ccccc4)c(OC)c3)C1)CC2
Solvent: CC(=O)O
Product: COc1cc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)ccc1O

Procedure:
Prepared from 3-[(N-(2-(4-benzyloxy-3-methoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-I,3,4,5-tetrahydro-2H-3-benzazepin-2-one in glacial acetic acid analogously to Example 8.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>O>[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[C:6]([OH:1])=[O:7]
Reactant: [OH-]
Reactant: COc1ccc(C=O)c(F)c1
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Into a warm (55° C.) mixture of Ag2O (13.5 g, 58.4 mmol), NaOH (19.5 g, 487 mmol) and water (200 mL) was added 2-fluoro-4-methoxybenzaldehyde (15 g, 97.4 mmol). The mixture was stirred for 1 h, filtered off and the precipitated solids were washed with hot water (10 mL). The filtrate was added slowly into cold (0° C.) HCl (5N) with vigorous stirring. The precipitated solid was filtered, washed with water and dried to give a white solid (13.6 g, 82% yield, m.p. 194–196° C.); MS m/e 169 (M−H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCBr
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1O
Yield: 89.3 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.840 ml (5.181 mmol) of heptyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/) to obtain 224 mg (0.4628 mmol, 89%) of 2-heptyloxy-2'-hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.85 (3H, t, CH3), 1.0-2.2 (14H, m, 7CH2), 2.35 (4H, t, 2CH2), 2.64 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 4.01 (2H, s, CH2), 6.61 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 483 (M-H)-
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.Cl[CH2:23][C:24]#[N:25]>CN(C=O)C>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:23][C:24]#[N:25])=[O:15])(=[O:19])=[O:18]
Reactant: N#CCCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Solvent: CN(C)C=O
Product: N#CCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
In a similar manner to Example 2, furosemide can be reacted with chloroacetonitrile in DMF to yield cyanomethyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]-benzoate.
Reaction SMILES: C(OC1C=C2C(=CC=1)NC1C(C)(CC(O)=O)OCCC2=1)C1C=CC=CC=1.[ClH:27].C([O:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH2:45][CH3:46])[C:40]1[C:47]([CH2:52][CH2:53][N:54]([CH3:56])[CH3:55])([CH3:51])[O:48][CH2:49][CH2:50][C:39]2=1)C1C=CC=CC=1>>[ClH:27].[CH3:56][N:54]([CH3:55])[CH2:53][CH2:52][C:47]1([CH3:51])[C:40]2[N:41]([CH2:45][CH3:46])[C:42]3[C:38]([C:39]=2[CH2:50][CH2:49][O:48]1)=[CH:37][C:36]([OH:35])=[CH:44][CH:43]=3
Reactant: CCn1c2c(c3cc(OCc4ccccc4)ccc31)CCOC2(C)CCN(C)C
Agent: CC1(CC(=O)O)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: Cl
Product: CCn1c2c(c3cc(O)ccc31)CCOC2(C)CCN(C)C

Procedure:
By following the procedure of this example but replacing 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid with an equivalent amount of 6-benzyloxy-1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, described in Example 731b, then 1-[2-(dimethylamino)ethyl]9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-ol hydrochloride, is obtained m.p. 213° - 214° C.; the corresponding free base of the latter compound has nmr (CDCl3) δ 1.36 (t, J = 7 cps, 3H) 1.6 (s, 3H), 2.18 (s,6H). Likewise, replacement with 6-benzyloxy-1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride described in Example 731d, gives 1,9-dimethyl-1-[2-(dimethylamino)ethyl]1,3,4,9-tetrahydropyrano[3,4-b]indol-6-ol hydrochloride, m.p. 242°-244° C., corresponding free base has nmr (CDCl3) δ 1.6 (s, 3 H), 2.2 (s, 6H), 3.7 (s, 3H).