Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])=[O:17]
Reactant: CC(C)=CCO
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CCOC(=O)CBr
Temperature: 0 °C
Yield: 64.2 %

Procedure:
A 1-liter flask was charged with 43.9 g (0.51 mol) of 3-methyl-2-buten-1-ol, 51.6 g (0.51 mol) of triethylamine and 300 ml of dichloromethane, and the mixture was cooled down to 0° C. While stirring the mixture at 0° C., 100.9 g (0.50 mol) of bromoacetyl bromide were added dropwise over 1 hour, followed by stirring further for 3 hours at room temperature. Solids were separated by filtration from the resultant reaction mixture, and the filtrate was washed 3 times with water and distilled to obtain 66.5 g of 3-methyl-2-butenyl bromoacetate.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17](Cl)[CH3:18])[CH3:10].C(OC([O-])=O)(OC(C)(C)C)=[O:21].C(OC(Cl)C)C.[OH2:37]>CN(C)C=O.C(OCC)(=O)C>[OH:37][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]([OH:21])[CH3:18])[CH3:10]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O
Reactant: CC(Cl)OCCCCOC(C)Cl
Agent: CCOC(C)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)OCCCCOC(C)O
Reaction time: 0.5 h

Procedure:
The thus obtained partially hydroxycarbonylmethylated polyhydroxystyrene, 90 g, was dissolved in 180 g of N,N-dimethylformamide. With stirring under ice cooling, 49.5 g of triethylamine and then 1.9 g of 1,4-butane diol di(1-chloroethyl) ether were added. Reaction was carried out for 30 minutes under ice cooling, 13.6 g of tert-butyl dicarbonate was added, and reaction was carried out for a further 2 hours at 40° C. After the reaction mixture was allowed to cool down, 23.2 g of 1-chloroethyl ethyl ether was added and reaction was carried out for 2 hours at room temperature. To the reaction mixture were added 500 g of ethyl acetate and 300 g of water, followed by separation. The ethyl acetate layer was washed twice with 300 g of water and then concentrated in vacuum. The residue was dissolved in 300 g of methanol and added dropwise to 20 liters of water whereupon a powdery solid precipitated. The solid was collected by filtration, washed with 20 liters of water, and dried in vacuum at 40° C. for 24 hours. On 1H-NMR analysis, it was identified to be a polymer (Polym. 10) in which 24.0 mol % of the hydrogen atoms of hydroxyl groups in polyhydroxystyrene were replaced by 1-ethoxyethyl groups, 7.0 mol % were replaced by tert-butoxycarbonyl groups, and the carboxyl group moieties which had been introduced in an amount of 2.0 mol % formed ester bonds with alcoholic hydroxyl groups of 1,4-butane diol di(1-hydroxyethyl) ether to provide crosslinking.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCC1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC1CCN(Cc2ccccc2)CC1
Yield: 83.9 %

Procedure:
2.58 g (11.1 mmol) of 1-benzyl-4-hydroxypropylpiperidine and 3.26 ml (23.4 mmol) of triethylamine were dissolved in 50 ml of tetrahydrofuran, and 1.67 ml (21.6 mmol) of methanesulfonyl chloride wasaddeddropwise. After completion of the reaction, the mixture was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, and then evaporated, to give a crude product. The crude product was subjected to 50 g of Cromatorex NH silica gel (ethyl acetate:hexane=1:1), to give 2.90 g (9.31 mmol, 83.9%) the title compound as a yellow oil. The physico-chemical data of the target compound was as indicated below.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH2:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CCOCC.[Cl:29][C:30]([Cl:35])([Cl:34])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:31](=[O:32])[C:30]([Cl:35])([Cl:34])[Cl:29])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(Cl)cc1C(=O)C1CCCCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a solution of 14.3 g of 2-amino-5-chlorophenyl cyclohexyl ketone and 6.0 g of triethylamine in the mixture of 100 ml of ether and 30 ml of methylene chloride was added dropwise with ice-cooling 11.0 g of trichloroacetyl chloride. After the mixture was stirred at room temperature for 2 hours, the organic layer was washed with water and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure to give oily residue. The residue was crystallized from ether to obtain 18.5 g of 2-trichloroacetamido-5-chlorophenyl cyclohexyl ketone as light yellow crystals, m.p. 93.0°-93.5°C.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C>N(CCO)(CCO)CCO.C(#N)C>[CH3:15][O:14][C:12](=[O:13])[C@@H:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:16]([OH:18])[CH3:17]
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Solvent: CC(C)O
Solvent: CC#N
Solvent: OCCN(CCO)CCO
Product: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Yield: 105 %

Procedure:
A 250 ml 3-neck flask with overhead stirrer was charged with methyl 2-benzamidomethyl-3-ketobutyrate (25 g), isopropylalcohol (37.5 ml) and 0.1 M triethanolamine(chloride)/0.04 M MgSO4 buffer pH7.2 (30 ml). The reaction mixture is stirred and temperature brought up to 37° C. using an oil bath. The reaction is started with the addition of 0.5 ml 19 g/L NADP-Na followed by 2.5 ml 30 g/L KRED of SEQ ID No. 10; both as solutions in 0.1 M triethanolamine (chloride)/0.04 M MgSO4 buffer pH 7.2. The reaction progress was followed by taking 5 μl aliquots over the course of the reaction that were diluted with 1 ml acetonitrile, filtered through a 0.25 μm syringe filter and analyzed as described in Example 3. When the conversion exceeded 96% saturated aqueous sodium chloride (12.5 ml) was added to the reaction mixture, followed by 40 ml ethyl acetate. The reaction mixture was stirred for another 15 minutes, then filtered through a Celite pad (5 g in a flitted glass filter) under vacuum. The filter cake was washed with 20 ml ethyl acetate and the two phases of the filtrate allowed to separated. The organic layer is washed three times with 20 ml water and concentrated on a rotary evaporator to an oil of constant weight. After removal of ethyl acetate, toluene (10 ml) was added and distilled under vacuum. (2S,3R)-methyl-2-benzamidomethyl-3-hydroxybutyrate (26.47 g) was obtained as an oil containing ˜10% toluene as determined by 1H-NMR—CDCl3.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:26]([C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([CH3:38])=[CH:40][CH:41]=1)[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN(C)C(=O)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-{[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate (500 mg, 1 eq.) in methylene chloride (5 ml), was added 4-methyl benzoyl chloride (380 ul, 3 eq.) and triethylamine (660 ul, 5 eq.). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude product was dissolved in ethyl acetate. Ethyl acetate layer was washed with water, saturated sodium carbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated to yield crude tert-butyl 3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:10])[O:13][CH2:12][CH2:11][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2cccc(Br)c2)OCCO1

Procedure:
30.1 g (151 mmol) of (3-bromophenyl)methyl ketone and 13.8 g (222 mmol) of ethylene glycol are dissolved in 120 mL of benzene, mixed with 60 mg of 4-toluenesulphonic acid and boiled under reflux at a water separator (Dean-Stark apparatus) until no more water is separated off. The reaction solution is washed with 50 mL of a 0.5 M NaHCO3 solution, the organic phase is separated off and dried over anhydrous MgSO4. After removal of the benzene in a rotary evaporator, the residue becomes the product with a purity (GC) of 97% in nearly quantitative yield as colorless oily liquid. C10H11O2Br.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:24]2[CH:23]=[CH:22][C:21]3[O:16][CH2:17][CH2:18][O:19][C:20]=3[CH:25]=2)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)OCCO3)n1
Reaction time: 24 h
Yield: 69 %

Procedure:
To a solution of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine (95 mg, 0.39 mmoles) in tetrahydrofuran (2 ml) was added a solution of 1,4-benzodioxan-6-amine (64 mg, 0.42 mmoles) and triethylamine (0.07 ml, 0.50 mmoles) in tetrahydrofuran (0.5 ml). After stirring for 24 hours, the mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with a solution composed of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1:1, 2×10 ml), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate-hexanes to provide CT-32028 (97 mg, 69% yield). 1H NMR (d6-DMSO) δ 9.88–10.28 (m, 2 H), 7.60–7.85 (m, 2 H), 7.20–7.40 (m, 3 H), 6.96–7.10 (m, 2 H), 6.77–6.81 (m, 1 H), 4.21 (s, 4 H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCCCC3)cc2C1

Procedure:
21.1 g (77 mmol) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (prepared as described in G. Grunewald et al. J. Med. Chem 1999, 42, 118-134) in 50 ml of THF were added dropwise to a solution of 6.0 g (70 mmol) of piperidine and 10.9 g (84 mmol) of diisopropylethylamine in 230 ml of THF, and the mixture was heated under reflux for two hours. After the reaction was complete, the solvent was removed in vacuo, the residue was taken up in dichloromethane/water and, after making alkaline with 10% strength sodium hydroxide solution and separating the phases, the organic phase was dried over sodium sulfate. The crude product remaining after filtration and removal of the solvent was purified by column chromatography on silica gel (mobile phase: methylene chloride with 3% methanol).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[CH2:4][CH:5]=[CH2:6].[C:14]([OH:17])(=[S:16])[CH3:15].CC(N=NC(C#N)(C)C)(C#N)C>N(C(C)(C)C#N)=NC(C)(C)C#N.O1CCOCC1>[C:14]([S:16][CH2:6][CH2:5][CH2:4][C:3]([C:8]([F:9])([F:10])[F:11])([C:2]([F:12])([F:13])[F:1])[OH:7])(=[O:17])[CH3:15]
Reactant: CC(O)=S
Reactant: C=CCC(O)(C(F)(F)F)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Product: CC(=O)SCCCC(O)(C(F)(F)F)C(F)(F)F
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, 20 g of 4,4-bis (trifluoromethyl)-4-hydroxy-1-butene (96.1 mmol), 8.05 g of thioacetic acid (105.7 mmol), 60 g of 1,4-dioxane and 0.79 g of 2,2′-azobisisobutyronitrile (hereinafter abbreviated as AIBN) (4.8 mmol) were put into a flask equipped with a stirring bar, a thermometer and a condenser, and heated with stirring. During the reaction, thioacetic acid and AIBN were appropriately added and after confirming that a substrate was completely consumed, the reaction solution was distilled as it was under reduced pressure to yield an intermediate product, 22 g of 4-acetylthio-1,1-bis (trifluoromethyl)-1-butanol (76.9 mmol).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.ClC1C=C([F:20])C=CC=1C=O.S1(CCCC1)(=O)=O.[F-].[K+]>>[F:10][C:4]1[CH:3]=[C:2]([F:20])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: O=Cc1ccc(Cl)cc1F
Agent: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=Cc1ccc(F)cc1F

Procedure:
158.5 g (1 mol) of a mixture of 56% of 4-chloro-2-fluoro-benzaldehyde and 44% of 2-chloro-4-fluorobenzaldehyde were heated together with 700 g of sulfolane and 75 g (1.29 mol) of potassium fluoride at 215° C. for 10 h. The working up was carried out as in Example 1. 99.5 g of 2,4-difluorobenzaldehyde equivalent to 70% of the feed-stock was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:19])[NH:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].CCN(CC)CC.ClC1C=CC([N:34]=[C:35]=[O:36])=CC=1C(F)(F)F.O>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:19])[NH:17][CH3:18])[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH2:34])=[O:36]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc(NC(N)=O)c(C)c2)ccn1
Reaction time: 144 h
Yield: 48.9 %

Procedure:
A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH2Cl2 (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl urea as a brown oil (0.11 g, 0.22 mmol): 1H NMR (DMSO-d6) δ2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 (d, J=2.9 Hz, 1H), 7.15 (dd, J=5.5, 2.6, Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.62 (app d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J=5.5 Hz, 1H), 8.78 (q, J=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([N:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOC(C)=O>[CH2:11]([N:18]1[C:19]2[CH:20]=[CH:21][C:22]([CH:3]=[O:4])=[CH:23][C:24]=2[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)c1ccccc1n2Cc1ccccc1
Temperature: 0 °C
Yield: 36.3 %

Procedure:
A 50-mL 3-necked round-bottomed flask was charged with N,N-dimethylformamide (400 mg, 5.42 mmol, 2.80 equiv, 99%). To this, POCl3 (700 mg, 4.56 mmol, 2.40 equiv, 99%) was added drop wise with stirring at 0° C. and allowed to stir at room temperature for 1 hour. To this mixture was added 9-benzyl-9H-carbazole (500 mg, 1.93 mmol, 1.00 equiv, 99%) in small portions at 45° C. over 5 minutes. Then, the temperature was raised to 95° C. in an oil bath and allowed to stir for 18 hours. The progress was monitored by TLC (EtOAc:PE=1:4). Upon completion, the reaction mixture was cooled down to room temperature and quenched with water (20 mL). The resulting mixture was allowed to stir for an additional 4 hours at room temperature. The solids were collected by filtration and dried to afford 9-benzyl-9H-carbazole-3-carbaldehyde as green solid (200 mg, 36.1%). LCMS: [M+H]+: 286
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:5][N:4]=[N:3]1.OO.S([O-])(O)=[O:21].[Na+].C(OO)=O.[OH2:29]>C(O)=O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:11]([CH2:10][CH2:9][CH2:8][S:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:21])=[O:29]
Reactant: O
Reactant: O=S([O-])O
Reactant: Cn1nnnc1SCCCSc1ccccn1
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O=CO
Product: Cn1nnnc1S(=O)CCCS(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-Methyl-5-[3-(2-pyridyl)thiopropyl]thio-1,2,3,4-tetrazole (2.2 g) is dissolved in formic acid (20 ml), and thereto is added with stirring 30% hydrogen peroxide (2.2 g) at room temperature. The mixture is stirred at room temperature for 5 hours, and thereto is added sodium hydrogensulfite under ice-cooling in order to decompose excess amount of performic acid. Water is added to the mixture and the mixture is extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography [Kieselgel 60, eluting agent, chloroform-methanol (50:1)] to give 3-(1-methyl-1,2,3,4-tetrazol-5-yl)sulfinylpropyl 2-pyridyl sulfoxide (0.5 g) as colorless liquid, nD28.5 =1.5795
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([N-]C(C)C)(C)C.[Li+].[CH:26]1([CH:29]=[O:30])[CH2:28][CH2:27]1>C1COCC1>[CH:26]1([CH:29]([OH:30])[CH:6]2[C:5](=[O:8])[C:4]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])=[C:3]([O:2][CH3:1])[CH2:7]2)[CH2:28][CH2:27]1
Reactant: O=CC1CC1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 152 %

Procedure:
To a stirred solution of 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (0.69, 3.0 mmol) in anhydrous THF (10 ml) at −78 C under an N2 atmosphere was added dropwise a solution of lithium diisopropylamide (1.75 ml of a 1.8M solution in THF/heptanes/ethyl benzene, 3.15 mmol). The reaction was stirred at −78 C for 60 minutes and then cyclopropanecarbaldehyde (0.27 ml, 3.6 mmol) was added dropwise. The reaction was stirred at −78 C for a further 30 minutes and then allowed to warm to room temperature over 210 minutes. The reaction was quenched by addition of H2O (50 ml) and extracted with EtOAc (50 ml). The organic phase was washed with H2O (50 ml) and brine (50 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give a brown oil (1.37 g). The crude material was purified by flash chromatography over SiO2 using a 100% isohexane to 100% EtOAc gradient to give the desired product (mix of diastereomers) as a colourless oil (622 mg).
Reaction SMILES: O.Cl.[CH3:3][C:4]1([CH3:23])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]1=2>[Zn].C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:23])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCC(=O)O)ccc21
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CCCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a mixture of 6 g zinc wool and 0.6 g of mercuric chloride, there are added 9 cm3 of water and 0.3 cm3 of 12N HCl. The mixture is stirred for 10 minutes at ambient temperature. The aqueous phase is removed by decanting. The resulting amalgam is rinsed with 20 cm3 of water. There are added 7.21 g (0.025 mole) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-oxo butyric acid, described in Example III, 10 cm3 of water, 8 cm3 of toluene and 5 cm3 of 12N HCl. The mixture is heated for 34 hours at reflux with stirring, adding 3 cm3 of 12N HCl every 6 hours. The reaction mixture is diluted by the addition of 100 cm3 of toluene, filtered (separation of residual amalgam) and rinsed with toluene. The toluene phase is separated, washed copiously with water, dried on sodium sulfate and concentrated under reduced pressure. The resulting crude oil is purified by chromatography on silica 60 gel in a 2/8/90 acetic acid/dioxan/toluene eluant mixture. After evaporation, the recovered solid is taken up in a minimum of isopropyl ether, filtered and dried under a vacuum at 70° C. 4.6 g of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) butyric acid in the form of a white solid whose melting point is 99° C. are obtained.
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.Br[C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][CH:27]=1>>[NH:32]1[C:33]2[C:29](=[CH:28][CH:27]=[C:26]([C:12]#[C:11][C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:34]=2)[CH:30]=[CH:31]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc3cc[nH]c3c2)c1)c1ccccc1
Yield: 17.9 %

Procedure:
In a manner similar to that described in Example 443, (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 6-bromoindole (90.7 mg, 0.46 mmol) were reacted to give the title compound (30 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:3][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[N:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)cn1
Solvent: ClCCl
Product: COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 216.1 %

Procedure:
Thionyl chloride (0.23 ml, 3.23 mmol) was added to a solution of (6-methoxypyridin-3-yl)methanol (1.10 g, 8.41 mmol) in DCM at 0° C. and the reaction mixture was stirred for 2 h at room temperature. After completion of reaction, the volatiles were evaporated and the reaction mixture was basified with saturated sodium bicarbonate solution. The compound was extracted with DCM (2×30 ml) and washed with brine (15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and dried to afford 1.1 g (88%) of 5-(chloromethyl)-2-methoxypyridine as a colorless liquid. This compound was directly taken to the next step.