Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)([OH:14])[C:6]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:5]=2[CH:4]=1.OS(O)(=O)=O.[OH-].[Na+]>>[Cl:26][C:24]1[CH:23]=[CH:22][C:6]2[C:7]([OH:14])([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:3](=[O:2])[CH2:4][C:5]=2[CH:25]=1.[ClH:26]
Reactant: COC1=Cc2cc(Cl)ccc2C(O)(C2CCN(C)CC2)c2ncccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(C2(O)c3ccc(Cl)cc3CC(=O)c3cccnc32)CC1
Product: Cl
Temperature: 25 °C

Procedure:
Dissolve 5-Methoxy-8-chloro-11-(1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol (4.26 g) in CH30H (6 mL) at 0° C. under an argon atmosphere. Add slowly a cooled solution of 92% aqueous H2SO4 (54 mL). Allow the mixture to warm to room temperature for 35 minutes. Pour the solution onto ice, basify with aqueous NaOH (25%), and extract with methylene chloride (3×). Combine the organic portions, wash with brine and dry over sodium sulfate. Filter and concentrate in vacuo. Triturate the residue with isopropyl ether to give an intermediate, 8-chloro-11-hydroxy-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one as a white solid (3.58 g., 92%, m.p. 170° to 174° C. as HCl salt).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][CH:12]=[N:11][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:23][C:24]([F:28])([F:27])[CH2:25]I>CN(C=O)C.O>[C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:25][C:24]([F:28])([F:27])[F:23])[CH:12]=[N:11][C:10]=3[O:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]cnc2occ(-c3ccccc3)c12
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(-c3ccccc3)coc2ncn1CC(F)(F)F
Temperature: 70 °C
Yield: 26.3 %

Procedure:
To a solution of 5-phenylfuro[2,3-d]pyrimidin-4(3H)-one (2 g, 9.42 mmol, prepared as described in WO2006/004658) in DMF (20 ml) was charged cesium carbonate (6.76 g, 20.7 mmol) and 1,1,1-trifluoro-2-iodoethane (1.86 ml, 18.9 mmol). The reaction was heated at 70° C. for 18 h under a nitrogen atmosphere. A further 1 eq. of 1,1,1-trifluoro-2-iodoethane was charged to the reaction mixture. The reaction was heated to 100° C. for 5 h before being cooled to RT, diluted with water and extracted twice with ethyl acetate. The organic extracts were washed with brine (3×50 ml), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by silica gel chromatography (SiO2, 0 to 50% EtOAc in cyclohexane) affording the title compound as a beige solid (730 mg, 26%). LCMS RT=1.27 min, M+H+=295.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(Cl)(Cl)Cl)cc1
Product: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1

Procedure:
Reaction of 4-trichloromethylbenzoic acid with thionyl chloride affords 4-trichloromethylbenzoyl chloride, which, on reaction with diethylamine, affords 4-trichloro-methyl-N,N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl 10 lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 4-trichloromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 6-trichloromethylsaccharin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]1[N:14]([CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])[CH2:13][CH2:12][N:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH:10]12>>[ClH:1].[ClH:1].[CH2:9]1[N:14]([CH2:15][CH2:16][CH2:17][C:18]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)=[O:19])[CH2:13][CH2:12][N:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH:10]12
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Product: Cl
Product: O=C(CCCN1CCN2CCCCC2C1)Nc1cccc(Cl)c1

Procedure:
The procedure is as for Example 2 using as substrate 3-chloroaniline and the compound obtained in Step B of Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11]([O:14][CH3:15])(=[O:13])[CH3:12].C[O-].[Na+].S(=O)(=O)(O)O>CCCCCCC.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:4]([CH:3]([CH2:8][CH2:7][CH2:6][CH3:9])[CH2:15][O:14][C:11](=[O:13])[CH:12]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:5]
Reactant: COc1ccc(C=O)cc1
Reactant: COC(C)=O
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Yield: 83 %

Procedure:
U.S. Pat. No. 5,527,947 describes a process in which C1-C4-alkoxybenzaldehydes, such as anisaldehyde, and C1-C4-alkyl acetates, such as methyl acetate, are dissolved in an inert hydrocarbon, such as heptane, toluene or petroleum ether. In the presence of a strongly alkaline metal base, such as sodium methoxide, the feed substances react to give a mixture of the corresponding C1-C4-alkyl-C1-C4-alkoxy cinnamates, the alkali metal salts of the corresponding C1-C4-alkoxy cinnamic acid and the C1-C4-alkanols. Following acidification of the reaction mixture with a strong polybasic acid, such as sulfuric acid, the liberated acetic acid is esterified with the C1-C4-alkanoles and distilled off. The mixture of C1-C4-alkyl-C1-C4-alkoxycinnamates and C1-C4-alkoxycinnamic acids which remains is reacted with a C5-C14-alkanol in the presence of a metal salt of a strong polybasic acid, such as sulfuric acid. Following transesterification and esterification, the corresponding C5-C14-alkyl-C1-C4-alkoxycinnamate, e.g. 2-ethylhexyl-4-methoxycinnamate, is obtained with 83 to 87% yield.
Reaction SMILES: C[Si](C)(C)[S:3][Si](C)(C)C.C[O-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[N:25]1[C:29]([NH:30][CH3:31])=[C:28]([CH:32]2[S:36][CH2:35][CH2:34][S:33]2)[C:27]([C:37]#[N:38])=[N:26]1>CN(C)C=O.CCOCC.O>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:19]=[C:14]([Cl:13])[C:15]=1[N:25]1[C:29]([NH:30][CH3:31])=[C:28]([CH:32]2[S:33][CH2:34][CH2:35][S:36]2)[C:27]([C:37](=[S:3])[NH2:38])=[N:26]1
Reactant: C[Si](C)(C)S[Si](C)(C)C
Reactant: CNc1c(C2SCCS2)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CNc1c(C2SCCS2)c(C(N)=S)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To 1,1,1,3,3,3-hexamethyldisilathiane (0.157 g, 0.9 mmol) in dimethylformamide (4 mL) was added sodium methoxide (0.049 g, 0.9 mmol) and the resulting mixture was sonicated to provide a homogeneous blue colored solution. This resulting solution was added to the solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(1,3-dithiolan-2-yl)-5-(methylamino)-1H-pyrazole-3-carbonitrile (0.08 g, 0.2 mmol) in dimethylformamide (5 mL) at room temperature under nitrogen. This mixture was stirred at room temperature for one and half hour. It was then diluted with ether (30 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with ether. The ethereal layers were combined and washed twice with water (2×20 mL), dried (Na2SO4), and concentrated to provide a yellow solid. Upon chromatographic purification via silica gel eluting with heptane:ethyl acetate (4:1 to 2:1), a yellow solid (0.048 g, 55%) was obtained. 19F-NMR: −63.634.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH:47]=[CH:46][CH2:45][N:44]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH:47]=[CH:46][CH2:45][N:44]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CC=CCN(Cc2ccccc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=CCN(Cc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S,Z)-1-benzyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 51 (5.9 mg, 0.027 mmol) to give a white solid (10 mg, 68% yield). Anal. Calcd. for C44H52N4O6S m/z 764.4. found: 765.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.06 (m, 16H), 6.96 (d, J=7.1 Hz, 1H), 5.67-5.48 (m, 2H), 5.34 (t, J=4.6 Hz, 1H), 5.18-5.06 (m, 2H), 5.05-4.93 (m, 1H), 4.61 (dd, J=51.2, 15.0 Hz, 2H), 4.34 (d, J=17.6 Hz, 1H), 3.67 (s, 3H), 3.33 (dd, J=17.6, 6.8 Hz, 1H), 3.14 (t, J=11.4 Hz, 1H), 2.91-2.64 (m, 4H), 2.51-2.14 (m, 6H), 2.02 (d, J=4.4 Hz, 2H), 1.89-1.44 (m, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.O1CCCC1.[H-].[Na+].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>O.CN(C)C=O>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:23][CH:22]=1
Reactant: Nc1ncccc1-c1cn[nH]c1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
To a mixture of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (150 mg, 0.94 mmol) described in Manufacturing Example 32-1-4 and tetrahydrofuran (2 mL) was added sodium hydride (12 mg, 0.24 mmol, 50% in oil) at 0° C., and then N,N-dimethylformamide (2 mL) was added. The reaction mixture was stirred for 10 minutes at room temperature, after which 4-bromobenzyl bromide (260 mg, 1.0 mmol) was added at 0° C. to this mixture, which was stirred for 1 hour at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1) to obtain the title compound (270 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:13][CH2:14][N:15]([C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:27])[CH2:16][CH2:17]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Clc1ccc2nccc(N3CCNCC3)c2c1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3ccc(Cl)cc23)CC1

Procedure:
6-Chloro-4-(piperazin-1-yl)quinoline (0.25 g, 1.0 mmol), 4-fluorophenyl isocyanate (170 μL, 1.5 mmol), and DMAP (2 mg) in THF (10 mL) are reacted according to method C yielding the product as a colorless solid after column chromatography with hexane-EtOAc. 1H NMR ([D]6-DMSO), δ 3.17 (m, 4H), 3.75 (m, 4H), 7.08 (t, 2H), 7.10 (d, 1H), 7.46 (dd, 2H), 7.72 (dd, 1H), 7.98 (d, 1H), 8.01 (d, 1H), 8.68 (br. s, 1H), 8.72 (d, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1cccc(OCCCBr)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.723 g of 1-(3-bromopropoxy-3-fluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.29.
Reaction SMILES: Br[C:2]1([CH2:10][C:11]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:7])[O:5][C:4]([CH3:9])([CH3:8])[O:3]1.N12CCCN=C1CCCCC2>O1CCCC1>[CH3:8][C:4]1([CH3:9])[O:5][C:6](=[O:7])/[C:2](=[CH:10]/[C:11]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])/[O:3]1
Reactant: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)/C(=C/C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl ester (˜26 g, 52.4 mmol) in dry tetrahydrofuran (160 ml) was cooled to 0° C. and treated dropwise over 5 minutes with 1,8-diazabicyclo [5,4,0]undec-7-ene (12.7 g, 78.8 mmol) and the resulting mixture was stirred at 5° C. for 1.5 hour. The solid formed was filtered and washed with a small amount of tetrahydrofuran. The filtrate was used as such for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[OH:29][C:30]1[CH:35]=[C:34]([CH3:36])[O:33][C:32](=[O:37])[CH:31]=1>CN(C)C1C=CN=CC=1.ClCCCl>[OH:29][C:30]1[CH:35]=[C:34]([CH3:36])[O:33][C:32](=[O:37])[C:31]=1[C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc(O)cc(=O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: Cc1cc(O)c(C(=O)Cc2cccc([N+](=O)[O-])c2)c(=O)o1
Reaction time: 1 h
Yield: 57.6 %

Procedure:
3-Nitrophenylacetic acid (7.20 g, 39.6 mmol) and then dicyclohexylcarbodiimide (8.6 g, 42 mmol) were added to a 1,2-dichloroethane (100 ml) suspension of 4-hydroxy-6-methyl-2-pyrone (5.00 g, 39.6 mmol) at room temperature, then 4-dimethylaminopyridine (0.24 g, 2.0 mmol) added and stirring carried out for 1 hour at 60° C., after which further 4-dimethylaminopyridine (0.48 g, 4.0 mmol) was added and stirring performed for 6 hours at 60° C. While the solution was still warm, the dicyclohexylurea was filtered off, and the reaction solution washed with dilute hydrochloric acid (50 ml), after which the aqueous layer was extracted with dichloromethane. After drying with anhydrous sodium sulphate, the solvent was distilled off and separation and purification carried out column chromatography. When recrystallization was performed from ethanol, 4-hydroxy-6-methyl-3-(3-nitrophenylacetyl)-2-pyrone (6.60 g, 58%) was obtained as white crystals.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[CH2:21]([C:23]([CH2:25][CH3:26])=O)[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:21]([C:23]1([CH2:25][CH3:26])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3)[CH3:22]
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1(CC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C

Procedure:
A mixture consisting of 5-benzyloxytryptophol (7.0 g, 0.0262 mol), diethyl ketone (10 mL), benzene (400 mL) and p-toluene sulfonic acid is refluxed for 3.5 hours using a Dean-Stark tap to remove the water. The reaction mixture is cooled to room temperature, washed with 5% sodium bicarbonate, water (200 mL), brine (200 mL), dried (MgSO4), filtered and concentrated to give 9.9 g of crude product. The crude product is flash chromatographed on silica gel using 15% ethyl acetate/hexane as an eluent to afford 6.5 g of pure title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15]([C:17]1[S:18][CH:19]=[C:20]2[C:26]=1[C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[O:23][C:22]1[CH:31]=[CH:32][CH:33]=[CH:34][C:21]2=1)=O)C>O>[C:17]1([CH2:15][OH:14])[S:18][CH:19]=[C:20]2[C:26]=1[C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[O:23][C:22]1[CH:31]=[CH:32][CH:33]=[CH:34][C:21]2=1
Reactant: CCOC(=O)c1scc2c1-c1ccccc1Oc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1scc2c1-c1ccccc1Oc1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of LiAlH4 in dry ether (10 mmoles in 15 ml of dry ether) an ether solution of the ester 5 (2 mmoles in 15 ml of dry ether) was added drop by drop. The reaction mixture was stirred at room temperature for 4 hours. After the complete quantity of the ester had been reacted (the course of the reaction was followed by thin layer chromatography), the excess of LiAlH4 was decomposed by the addition of diethyl ether and water. The obtained white precipitate was filtered off and after drying on anhydrous Na2SO4 the filtrate was evaporated under reduced pressure. The crude product was purified by chromatography on a column to give a pure product in the form of yellowish crystals.
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH:6](=O)[CH3:7].[CH3:9][O:10][CH2:11][CH2:12][NH2:13].[C-:14]#[N:15].[K+]>O>[CH3:9][O:10][CH2:11][CH2:12][NH:13][CH:6]([CH3:7])[C:14]#[N:15]
Reactant: CC=O
Reactant: [C-]#N
Reactant: COCCN
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COCCNC(C)C#N
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
To a stirred solution of 62.4 g (0.6 mole) sodium bisulfite in 200 ml water which had been cooled in an ice bath, 26.5 g (0.6 mole) acetaldehyde were added over 5 minutes. The ice bath was removed. The reaction mixture was stirred 2.5 hours; then 45 g (0.6 mole) 2-methoxyethylamine were added (with evolution of heat). The reaction mixture was stirred 2 hours; then 39 g (0.6 mole) potassium cyanide were added with heat evolution and the resulting mixture was stirred at ambient temperature. After about 30 minutes, a second phase separated; the reaction mixture was stirred 3 hours and then allowed to stand overnight. The reaction mixture was extracted with 150 ml methylene chloride. The methylene chloride extract was dried over magnesium sulfate and stripped to give 67.4 g of the light yellow oil. The oil was distilled under vacuum to give 60.6 g of the above-identified product as a clear, colorless oil, boiling at 60° C. at 0.20 mm.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14][CH:15]2[CH2:20][NH:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:26](Cl)(=[O:28])[CH3:27].Cl>C(Cl)Cl>[C:26]([N:19]1[CH2:20][CH:15]([CH2:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:16][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)C1CNCC(CC2CCCCC2)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(CC2CCCCC2)CN(C(C)=O)C1
Temperature: 25 °C

Procedure:
Triethylamine (410 μL, 2.9 mmol) was added to a solution of ethyl 5-(cyclohexylmethyl)piperidine-3-carboxylate (180 mg, 0.71 mmol) and acetyl chloride (120 mg, 1.4 mmol) in CH2Cl2 (10 mL). The reaction was maintained at room temperature for 30 min before being diluted with CH2Cl2 (20 mL) and poured into HCl (1 N, 20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were sequentially washed with H2O (10 mL) and brine before being dried over Na2SO4. Concentration under reduced pressure and purification by silica gel chromatography (hexane→80% EtOAc/hexane) provided the title compound as a yellow oil. MS m/z: 296.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:8][CH2:9][OH:10])=[CH:5][S:6][CH:7]=1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:8][CH2:9][O:10][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:5][S:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cscc1CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cscc1CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
Into a 500 ml three-necked flask (reaction container) with thermometer and dropping funnel, 7.72 g (48.8 mmol) of 2-(4-methoxythiophene-3-yl)ethane-1-ol represented by the formula (VI-A) shown below, 11.58 g (146 mmol) of pyridine, and 135 ml of methylene chloride were transferred. The reaction container (flask) was cooled in an ice bath, then 50 ml of methylene chloride containing 18.6 g (97.6 mmol) of p-toluene sulfonic chloride was added dropwise over a period of 10 minutes, then the ice bath was removed from the flask. The reaction solution was stirred at room temperature for a period of 1.5 hours. After the reaction was completed, 100 ml of water was added to separate the organic layer from the water layer. The organic layer was washed twice each with 100 ml of water, then washed twice with saturated aqueous sodium hydrogen carbonate and then dried over anhydrous sodium sulfate. Then it was condensed under a reduced pressure, thereby obtaining a crude product. This crude product was purified using silica gel column chromatography to obtain p-toluene sulfonic acid-2-(4-methoxythiophene-3-yl)ethyl ester (10.5 g, 33.6 mmol, yield 68.9%), a thiophene derivative represented by the formula (IV-A) having properties described below. The chemical equation (X-A) is shown below.