Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:3].S(Cl)([Cl:24])=O>>[CH3:1][N:2]([CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([Cl:24])=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CN(C)Cc1ccccc1Oc1cccc(CC(=O)O)c1
Product: CN(C)Cc1ccccc1Oc1cccc(CC(=O)Cl)c1

Procedure:
2 g of 3-(2-dimethylaminomethylphenoxy)-phenylacetic acid are treated with 20 ml of thionyl chloride and heated with stirring and under reflux for 1/2 an hour. The solvent is then removed. The residue is taken up with toluene and the solvent is again distilled off.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12](=[CH2:15])[CH2:13][OH:14].[OH-].[K+].O>CS(C)=O>[CH3:15][C:12]([CH2:13][O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])=[CH2:11]
Reactant: C=C(C)CO
Reactant: N#Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=C(C)COc1cccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
A solution of 30.0 grams (0.174 mole) of 2,6-dichlorobenzonitrile and 14.7 mL (0.174 mole) of 2-methyl-2-propen-1-ol in 200 mL of dimethyl sulfoxide was stirred, and 12.7 grams (0.191 mole) of 85% potassium hydroxide was added portionwise during a 5 minute period. During the addition, the reaction mixture temperature rose from 20° C. to about 35° C. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into 600 mL of water. The mixture was filtered to collect a solid. The solid was washed with water and dried under vacuum, yielding 33.9 grams of 2-methyl-3-(3-chloro-2-cyanophenoxy)-1-propene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[N:12]O)[CH2:3]1)[CH2:9]2.[H][H]>CCO.[Rh]>[NH2:12][CH:5]1[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2
Reactant: ON=C1C2CC3CC1CC(O)(C3)C2
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: NC1C2CC3CC1CC(O)(C3)C2
Yield: 97.8 %

Procedure:
Rh/Al2O3 (2.3 g, 5 wt. %, 1.1 mmol) was added to a mixture of 5-hydroxy-admantane-2-one oxime (10 g, 55 mmol) in EtOH (100 mL) in a Parr hydrogenation bottle. The hydrogenation reaction was performed in a Parr hydrogenation instrument at 55 psi pressure of hydrogen at 50° C. for 48 hours. The disappearance of starting material and generation of the product were detected by LC-MS. The mixture was filtered through celite and concentrated under vacuum to dryness to give 4-amino-adamantan-1-ol (about 9 g, ˜98%) which was used for the next step without further purification. Mass spectrum: m/z: 168.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:21][C:20]([CH3:22])=[N:19][C:18]=3[CH:23]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[CH3:22][C:20]1[S:21][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:23][C:18]=2[N:19]=1
Reactant: Cc1nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(N3CCNCC3)ccc2s1

Procedure:
Prepared in analogy to example 1.6 (d) from 4-(2-methyl-benzothiazol-5-yl)-piperazine-1-carboxylic acid tert.-butyl ester and dioxane saturated with gaseous hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.Cl.[CH2:18]([N:20]([CH2:33][CH3:34])[CH2:21][CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][N:20]([CH2:33][CH3:34])[CH2:18][CH3:19])=[CH:32][CH:31]=3)[C:6]=2[CH:16]=1
Reactant: Clc1ccc2oc(-c3ccccc3)cc2c1
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
Acylation of 5-chloro-2-phenylbenzofuran with 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride as described in the procedure of Example 6 gives the title compound which is converted to the corresponding hydrochloride salt as described in the procedure of Example 1, m.p. 197°-199° (ethyl acetate).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:22]=[C:23]([S:27]([NH:30][C:31]2[S:32][C:33]([CH3:36])=[N:34][N:35]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]1[CH:22]=[C:23]([S:27]([NH:30][C:31]2[S:32][C:33]([CH3:36])=[N:34][N:35]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(-c2ccc3c(-c4cccc(S(=O)(=O)Nc5nnc(C)s5)c4)c(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: Cc1nnc(NS(=O)(=O)c2cccc(-c3c(O)ccc4cc(-c5cccc(O)c5)ccc34)c2)s1
Yield: 47 %

Procedure:
The compound is prepared by the reaction of 3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)-N-(5-methyl-1,3,4-thiadiazole-2-yl)benzenesulfonamide (0.28 mmol, 1 eq) with boron tribromide solution (2.8 ml, 2.8 mmol, 10 eq) according to method G. Purification by column chromatography with dichloromethane/methanol 95/5 as the eluent yielded the desired compound in a yield of 47%, 64 mg.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>>[CH2:1]([NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Si:13]([CH3:15])([CH3:14])[CH3:12])[CH3:2]
Reactant: CCNC(=O)c1ccccc1
Reactant: C[Si](C)(C)Cl
Product: CCNC(=O)c1ccccc1[Si](C)(C)C
Yield: 68.3 %

Procedure:
N-Ethylbenzamide (74.5 g, 500 mmol) and TMSCl (135.8 g, 1.25 mol) were combined according to General Method C and purified by HPLC with 1:4 ethyl acetate/hexanes to afford 75.59 g of the title compound, as a white solid, a 68% yield. m.p. 64.0°-66.0° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([F:28])[C:26]=1[F:27])[NH2:23]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:23][C:22]3[CH:21]=[C:20]([F:19])[C:26]([F:27])=[C:25]([F:28])[CH:24]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)c(F)c(F)c1
Yield: 11.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 113 mg of 3,4,5-trifluoroaniline in place of the 2,4-difluoroaniline. 33 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(3,4,5-trifluorophenyl)acetamide are obtained, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=2)[C:3]=1[Cl:23].[NH:24]1C(=O)CC[C@H:25]1C(O)=O.Cl>>[Cl:23][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[CH:15]=2)=[N:5][C:6]2[C:11]([C:2]=1[C:25]#[N:24])=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COc1ccc2nc(-c3ccc(OC)c(F)c3)c(Cl)c(Br)c2c1
Agent: Cl
Product: N#Cc1c(Cl)c(-c2ccc(O)c(F)c2)nc2ccc(O)cc12
Yield: 41 %

Procedure:
This compound was prepared from 34b according to method F and method G (using Pyr./HCl). Yellow solid; Yield: 41% (for two steps); mp 325-328° C. (dec.); 1H-NMR (300 MHz, DMSO-d6) δ 7.10 (dd, J=8.8, 8.7 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.43 (dd, J=8.4, 1.4 Hz, 1H), 7.49 (dd, J=9.2, 2.5 Hz, 1H), 7.55 (dd, J=12.2, 2.0 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 10.37 (s, 1H), 10.97 (s, 1H); MS (ESI) m/z 313 ([M−H]−), 315 ([M+H]+); Anal. Calcd for C16H8ClFN2O2: C, 61.07; H, 2.56; N, 8.90. Found: C, 60.80; H, 2.57; N, 8.55.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:7][N:6]=1)=[O:4]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCl)cn1
Temperature: 25 °C

Procedure:
The solution of 13.8 g of 5-hydroxy-2-pyridinecarboxylic acid methyl ester in 200 ml of dimethylformamide is added over a period of 45 minutes to a suspension of 4.3 g of sodium hydride in (57% mineral oil dispersion) 50 ml of dimethylformamide with stirring at room temperature. The mixture is stirred at room temperature for one hour and then is cooled to 5°-10°. To this cooled mixture is added a solution of 19.3 g of 1-bromo-3-chloropropane in 100 ml of dimethylformamide. The mixture is heated to 45°-50° and stirred at 45°-50° for 4 hours and 30 minutes. After that, the mixture is cooled, filtered and the filtrate evaporated to a residue. The residue is partitioned between methylene chloride and water and the layers are separated. The methylene chloride layer is washed with water and dried over anhydrous sodium sulfate. The methylene chloride solution is filtered and the filtrate evaporated to yield 5-(3-chloropropoxy)-2 -pyridinecarboxylic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>O.[Fe]>[N:13]1([S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Yield: 94.2 %

Procedure:
To a stirred solution of 4-(4-nitro-benzenesulfonyl)-morpholine (5.0 g, 18.4 mmol) ethanol (400 mL) was added iron powder (5.2 g, 92.0 mmol) and the solution of ammonium chloride (10 g, 184.0 mmol) in water (100 mL). After the reaction mixture was refluxed for 3 h, the iron was filtered off and the filtrate was basified to pH 9 by addition of sodium carbonate. The reaction mixture was extracted with ethyl acetate (300 mL×2). The extract was washed with water (130 mL×2) and brine (130 mL×2), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 20-60% ethyl acetate in petroleum ether) to afford 4-(morpholine-4-sulfonyl)-phenylamine (4.2 g, 95%) as a yellow powder: MS (ESI) M+1=243.1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][CH2:14][OH:15]>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:14]1[C:13]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[O:15]1
Reactant: CCO
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: O
Product: O=C1OC(c2c(O)c3ccccc3oc2=O)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-chromen-2-one (650 mg) and 2-carboxybenzyladehyde (300 mg) in EtOH was heated to reflux for 4 hours, cooled to room temperature then concentrated in vacuo to give a crude oil, which was diluted with water. The precipitated 4-hydroxy-chromen-2-one was collected by filtration (490 mg). A second crop of solid was collected from the mother liquor and triturated with hot EtOAc and filtered to provide 4-Hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-chromen-2-one as white solid. MS: 293 [M−H].
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[Cl:34][Si](C)(C)C>CC(CC)=O>[ClH:34].[CH3:33][N:2]([CH3:1])[C:3]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CCC(c3c[nH]c4ccccc34)CC2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[4-(1H-indol-3-yl)-piperidine-1-yl]ethanone (344 mg, 0.779 mmole) was dissolved in ethyl methyl ketone (10 ml) and chlorotrimethylsilane (0.15 ml, 1.2 mmole) was added. After 45 minutes the hydrochloride was isolated as a beige-coloured solid with an m.p. of 178-180° C. in a yield of 65% (242 mg) (Example 26).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14](O)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: O=C1CCCc2c(O)cccc2N1
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2c1CCCC(=O)N2
Temperature: 25 °C
Yield: 87 %

Procedure:
A suspension of 1,3,4,5-tetrahydro-6-hydroxy-2H-1-benzazepin-2-one (500 mg, 2.82 mmol) in 2.5 mL each of pyridine and acetic acid was stirred at room temperature. Excess reagents were removed under reduced pressure and the residue was triturated with CH2Cl2 to give 540 mg (87%) of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-one; MS 219.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH:5]([N:7]1[CH2:12][CH2:11][C:10](=[CH2:13])[C:9]([CH3:15])([CH3:14])[CH:8]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:6]>ClCCl>[CH:5]([N:7]1[C@H:8]2[C@@:9]([CH3:14])([C:10]([CH3:11])([CH3:13])[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=3[CH2:16]2)[CH2:15][CH2:12]1)=[O:6]
Reactant: C=C1CCN(C=O)C(Cc2ccccc2OC)C1(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc2c1C[C@H]1N(C=O)CC[C@]1(C)C2(C)C
Temperature: 0 °C
Yield: 59.9 %

Procedure:
To a suspension of 88.0 g (0.66 mol) of aluminium trichloride in 420 mL of absolute dichloromethane is added dropwise, at 0-5° C., a solution of 60.1 g (0.22 mol) of N-formyl-2-(2'-methoxyphenyl) methyl-3,3-dimethyl-4-methylene-piperidine (4) in 200 mL of dichloromethane within 2 h. The mixture is left to react for a further 3 h at 5° C. and then poured onto 800 mL of ice. The organic phase is separated off and the aqueous phase is extracted twice more with 250 mL of dichloromethane. The combined organic phases are dried over MgSO4 and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (500 g silica gel, solvent: ethyl acetate). 36.0 g (60%) of trans-1-formyl-8-methoxy-3a, 4,4-trimethyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (5) are obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]2[CH:7]=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.C([Li])CCC.[C:22](=[O:24])=[O:23].[OH-].[Na+]>C1COCC1.CCCCCC.O>[CH3:13][C:11]1([CH3:14])[O:10][C:9]2[C:15]([C:22]([OH:24])=[O:23])=[C:4]3[O:3][C:2]([CH3:16])([CH3:1])[O:6][C:5]3=[CH:7][C:8]=2[O:12]1
Reactant: O=C=O
Reactant: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC1(C)Oc2cc3c(c(C(=O)O)c2O1)OC(C)(C)O3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole (10.0 g, 45.0 mmol; prepared according to WO-91/12024) was dissolved in dry THF (200 mL) under an argon atmosphere. The solution was cooled to -20° C. and n-butyllithium (20.0 mL, 50.0 mmol) in hexane was added. After attaining ambient temperature, the reaction mixture was transferred onto solid carbon dioxide (150 g) and allowed to stand overnight. Water (200 mL) was added and pH was adjusted to 10 using 2M aqueous NaOH. After washing with ether, the aqueous phase was acidified with 2M hydrochloric acid to pH 2 and extracted with ether (2*300 mL). The organic phases were dried (Na2SO4) and evaporated to give the pure product.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][C:5]1[CH:13]=[CH:14][C:2]([C:20]2[CH:21]=[CH:22][C:17]([CH:15]=[O:16])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc(OC3CCCCO3)cc2)cc1
Temperature: 95 °C
Yield: 45.2 %

Procedure:
2-(4-Bromophenoxy)tetrahydropyran (3.0 g) was dissolved in N,N-dimethylformamide (30 ml). 4-Formylphenylboronic acid (2.1 g), tetrakis(triphenylphosphine)palladium (0) (1.35 g) and tripotassium phosphate (4.95 g) were added thereto, and the resulting mixture was heated at 90 to 100° C. under a nitrogen atmosphere for 3 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture and filtered through Celite. The filtrate was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a white powder (1.49 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[C@@H:11]([OH:14])[C@H:10]([OH:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(C)[O-].COC(C)[O-].[H-].[Al+3].[Na+].COCCO[AlH2-]OCCOC.[Na+].[OH-].[NH4+]>C1COCC1.C(Cl)Cl.CCOC(C)=O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:14])[C@H:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Agent: COC(C)[O-]
Agent: COCCO[AlH2-]OCCOC
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Temperature: 25 °C

Procedure:
To a mechanically stirred and cooled solution (0° C.) of the product from Step 1 (50 g, 0.23 mol) in dry THF (1.24 L) was added sodium aluminum hydride bis-(methoxyethoxide) (289 mL of a 65% Red-Al®/Toluene solution, 0.95 mol) under a nitrogen atmosphere at such a rate that the internal temperature did not exceed 20° C. The reaction mixture was allowed stir at room temperature for 2 h after the addition was complete. The reaction mixture was slowly poured into ice water (1.0 L) with stirring to quench the reaction. After warming to room temperature, 30% ammonium hydroxide (100 mL) was added followed by EtOAc (1.5 L) and this mixture was stirred for 16 h. The suspension was filtered through diatomaceous earth and the solids were washed with EtOAc. The filtrate layers were separated and the organic phase was dried over sodium sulfate and concentrated to afford a syrup. Dissolution in methylene chloride and concentration affords a white solid that is collected and dried (43.7 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.23 (5H, m), 6.23 (2H, m), 4.65 (1H, m), 4.15-4.00 (3H, m), 3.62-3.49 (1H, dd), 3.33 (1H, dd), 3.14 (1H, dd), 2.94 (1H dd). MS m/z 194 (MH+).
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH2+:5][CH2:6][CH:7]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]=[S:31]>>[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]1[N:5]([CH2:6][CH:7]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4][CH2:3][S:31]1
Reactant: ClCC[NH2+]CC1CCCCCCCCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCCCCCCCC1

Procedure:
Methyl cyclododecanecarboxylate was reduced according to Method B2b, Step 1 to give cyclododecylmethanol. The alcohol was converted to cyclododecylmethylbromide according to Method B2b, Step 2. The halide was reacted with 2-hydroxyethylamine according to Method B2b, Step 3 to give N-(2-hydroxyethyl)-N-(cyclododecylmethyl)amine. The alcohol was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(cyclododecylmethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclododecylmethyl)-1,3 -thiazolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[CH:10]=1.[NH2:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([CH2:17][NH:19][CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:3]=1
Reactant: O=Cc1cc(F)cc2c1cnn2C1CCCCO1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(CCNCc1cc(F)cc2c1cnn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
To a solution of 6-fluoro-1-tetrahydropyran-2-yl-indazole-4-carbaldehyde (175 mg, 0.71 mmol) in MeOH (7 mL) was added tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (184 mg, 1.06 mmol). The reaction was stirred at RT for 4 h, and then NaBH4 (35.4 mg, 0.92 mmol) was added. The reaction mixture was stirred at RT for 4 h and water was added. MeOH was removed under reduced pressure and the residue was diluted with 1N NaOH solution. The aqueous solution extracted with twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to obtain crude tert-butyl (2-(((6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)amino)ethyl)(methyl)carbamate (300 mg, quantitative yield). MS (ESI) m/z: 407.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14]>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[C:9]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:12]=2[F:11])=[CH:8][S:7][CH2:6]1)=[O:4]
Reactant: Nc1ccc(I)cc1F
Reactant: COC(=O)C1CSCC1=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1CSC=C1Nc1ccc(I)cc1F
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A solution of methyl-4-oxo-tetrahydro-thiophene-3-carboxylate (5.75 g, 35.9 mmol) and 2-fluoro-4-iodo-aniline (9.4 g, 40.9 mmol) were heated to reflux in a mixture of ethanol (25 mL) and acetic acid (0.3 mL) for 18 hours. The solution was cooled to room temperature, filtered and the solid product dried in vacuo to provide methyl-4-(2-fluoro-4-iodo-phenylamino)-2,3-dihydro-thiophene-3-carboxylate (5.70 g, 42% yield). MS (EI) for C12H11FINO2S: 380 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>>[S:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1)(=[O:25])(=[O:24])[CH3:26]
Reactant: CCCOc1ccc(O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Product: CCCOc1ccc(OS(C)(=O)=O)cc1-c1nc(CC)c(CC)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 81 with mesyl chloride in the same manner as that of example 50. 1H NMR (CDCl3) δ: 8.39 (1H, d), 7.43 (1H, dd), 7.06 (1H, d), 4.18 (2H, t), 3.20 (3H, s), 2.68 (2H, q), 2.58 (2H, q), 2.00 (2H, m), 1.28 (3H, t), 1.14 (6H, t).