Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: C=CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 128 mg (1 mmole) of 6-heptenoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 175 mg (Yield: 44%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=O)N)[CH2:7]1)=[O:5])[CH3:2].[Br:17][C:18]1[N:23]=[C:22](C=O)[CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:17])[N:23]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=Cc1cccc(Br)n1
Reactant: CCN(CC)C(=O)C1CCCN(C(N)=O)C1
Product: CCN(CC)C(=O)C1CCCN(Cc2cccc(Br)n2)C1

Procedure:
14] N,N-Diethylcarbamoyl-piperidine-3-carboxamide (0.92 mL, 5.92 mmol) was added to a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) to give N,N-diethyl 1-(6-bromopyridin-2-ylmethyl)piperidine-3-carboxamide as a colorless oil. MS m/z: 354.1 (M+H). Calc'd for C16H24BrN3O—354.29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].O=[C:16]([CH3:20])[CH:17]=[N:18][OH:19].S([O-])([O-])(=O)=O.[Mg+2].C>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:16]([CH3:20])[CH:17]=[N:18][OH:19]
Reactant: CC(=O)C=NO
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C=NO)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (10.2 g) in ether (15 ml) was added with cooling to a solution of `2-oxopropanal 1-oxime (3.62 g) in ether (15 ml) at 0°. The mixture was stirred at room temperature overnight and magnesium sulphate and charcoal added. The mixture was filtered and solvent evaporated under reduced pressure. The residue was purified by column chromatography to give 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)propanal 1-oxime, m.p, c.108°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CS(C)=O.O>[S:19]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2ncc(-c3cc4ncccc4s3)n2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5ncccc5s4)n3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (40 mg, 0.139 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (20 mg, 0.139 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.695 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 40 mg of the yellow solid, 79%.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15]([CH:18]=O)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15](/[CH:18]=[C:27]3\[C:28](=[O:33])[NH:29][C:30]4[C:26]\3=[CH:25][C:24]([F:23])=[CH:32][CH:31]=4)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCN1CCCCc2[nH]c(C=O)c(C)c2C1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCN1CCCCc2[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 48.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diaz a-cyclopentacyclooctene-2-carbaldehyde 60e (20 mg, 0.066 mmol) was dissolved in 1 ml of ethanol under stirring, and added with 5-fluoro-1,3-dihydro-indol-2-one (9.9 mg, 0.066 mmol) to the solution at room temperature. The reaction mixture was stirred in dark until dissolved, added with 0.1 ml of piperidine, and heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, filtered to obtain the title compound (Z)-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentacycloocten-4-one 60 (14 mg, yield 48.8%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:19]([C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 2,4-dichlorobenzenesulphonyl chloride (0.13 g). Yield 0.045 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([NH:32][C:19]([C:18]2[CH:17]=[N:16][N:11]3[C:12]([CH2:14][CH3:15])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-ethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.26) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 455.92 [(M+H)+]; mp 230-232° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1.C1OC2C=CC([Mg]Br)=CC=2O1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34](=[O:41])[C:33]=3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:26][C:25]=2[O:24]1.Cl>C1COCC1.CCOCC.C1COCC1>[CH2:10]1[O:9][C:6]2[CH:7]=[CH:8][C:3]([C:34]3([OH:41])[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]([C:27]4[CH:28]=[CH:29][C:30]5[O:31][CH2:23][O:24][C:25]=5[CH:26]=4)=[C:33]3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:4][C:5]=2[O:11]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: Brc1ccc2c(c1)OCO2
Agent: Br[Mg]c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To dry magnesium turnings (0.25 g, 10 mmol) under an argon atmosphere was added a solution of 4-bromo-1,2-methylenedioxybenzene (2.1 g, 10 mmol) in 1:10 THF/Et2O (22 ml). The resulting solution was allowed to stir at room temperature for 2 h. During this time, additional THF (4 ml) was added. The resulting 3,4-methylenedioxyphenylmagnesium bromide was added to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.50 g, 2 mmol) in 1:4 THF/Et2O (25 ml) under an argon atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 15 min, at which time 1M HCl (50 ml) was added. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow solid (0.29 g, 42%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.S1C=CN=C1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:37][C:38]1[CH:45]=[C:44]([OH:46])[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]>CN(C)C=O.C(OC(=O)C)C>[Cl:37][C:38]1[CH:45]=[C:44]([O:46][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: FC(F)(F)c1ccc(-c2nc(COC3CCCCO3)c(CCl)s2)cc1
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cscn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
3.0 g 5-(Chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluormethyl)phenyl]-1,3-thiazole (synthesis is described in WO2002/067912) thiazole were dissolved in 100 ml dimethylformamide. 5.0 g of cesium carbonate and 1.53 g 2-Chloro-4-hydroxybenzonitrile were added and the mixture was stirred at room temperature overnight. Then 300 ml of ethylacetate were added, the mixture washed three times with saturated NaHCO3 solution and brine then dried over MgSO4. The solvent was removed in vacuo to obtain 4.1 g of crude 2-Chloro-4-[4-(tetrahydro-pyran-2-yloxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as yellow oil. This material was used without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=1.[F:23][C:24]1([F:45])[CH2:44][CH2:43][C:27]2([C:35]3([N:39]=[C:38]([NH2:40])[C:37]([CH3:41])=[N:36]3)[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([NH2:42])[CH:33]=3)[CH2:28]2)[CH2:26][CH2:25]1.Cl>C(Cl)Cl.CN(C=O)C>[NH2:40][C:38]1[C:37]([CH3:41])=[N:36][C:35]2([C:34]3[C:29](=[CH:30][CH:31]=[C:32]([NH:42][C:20]([C:17]4[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][N:18]=4)=[O:22])[CH:33]=3)[CH2:28][C:27]32[CH2:26][CH2:25][C:24]([F:45])([F:23])[CH2:44][CH2:43]3)[N:39]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC1=NC2(N=C1N)c1cc(N)ccc1CC21CCC(F)(F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1=NC2(N=C1N)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1CC21CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 17.2 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) was added to a suspension of 5-chloropicolinic acid (27 mg, 0.17 mmol) in DCM (0.5 mL). The obtained orange solution was stirred for 5 min and then added dropwise over 2 min to an ice-cooled solution of 4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine (Example 28d Step 1, 46 mg, 0.14 mmol) and 2M aq. HCl (0.072 mL, 0.14 mmol) in DMF (0.5 mL). The mixture was stirred at 0° C. for 10 min and was then allowed to reach r.t. overnight. The solvent was evaporated. The crude was purified using preparative chromatography to give the title compound (11 mg, 17% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (d, 1 H), 1.51 (d, 2 H), 1.66-1.98 (m, 5 H), 2.18 (s, 3 H), 2.99 (d, 1 H), 3.08 (d, 1 H), 6.63 (br. s., 1 H), 7.23-7.29 (m, 2 H), 7.62 (d, 1 H), 8.10 (d, 1 H), 8.18 (dd, 1 H), 8.74 (s, 1 H), 10.50 (s, 1 H); MS (APCI+) m/z 458.1 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Brc1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 58 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (10.0 g, 69.9 mmol, 1 eq) and 4-bromopyridine hydrochloride (16.2 g, 83.7 mmol, 1.2 eq) were dissolved in n-butanol (120 ml) and DIPEA (23 ml, 139.8 mmol, 2 eq) and refluxed for 14 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 3% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 58% (9.0 g, 40.9 mmol).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1>>[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)=[CH:33][N:32]=1
Reactant: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2nc(N3CCOCC3)c3nc(CN4CCN(S(C)(=O)=O)CC4)n(C)c3n2)cn1

Procedure:
4-(2-Chloro-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 2-methoxypyrimidin-5-ylboronic acid via General Procedure A and purified via reverse phase HPLC to give 5.5 mg 136 as a white solid. MS (Q1) 504.3 (M)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:34]I>O1CCCC1>[CH2:3]([O:10][CH2:11][CH:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[O:13][CH3:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC(COCCCCCCCCCCCCC1CCCCC1)COCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COCc1ccccc1

Procedure:
In 70 ml of tetrahydrofuran is suspended 0.86 g of sodium hydride, to which a solution of 10.2 g of 1-benzyl-3-(12-cyclohexyldodecyl)glycerine in 50 ml of tetrahydrofuran is added dropwise at room temperature with stirring. After 40 minutes stirring at room temperature, 5.11 g of methyl iodide is added and the mixture is further stirred for 2 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with hexane. The extract layer is washed with water, dried and concentrated to obtain crude 1-benzyl-2-methyl-3-(12cyclohexyldodecyl)glycerine which in turn is dissolved in a mixed solvent consisting of 100 ml of ethanol and 30 ml of acetic acid. The solution is shaked in the presence of 10% palladium-carbon under hydrogen streams. The catalyst is removed by filtration and the filtrate is concentrated to obtain 9.6 g of the captioned compound as a crude product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([O:24]C)=[O:23])(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34].Cl>C(#N)C>[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])[CH3:34]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCC2
Reactant: CCN(CC)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 200 °C

Procedure:
A mixture of Example 229A (143 mg, 0.393 mmol), triethylamine (0.165 mL), acetonitrile (1.2 mL), and N,N-diethyl-1,3-propanediamine (0.37 mL, 2.36 mmol) was sealed and heated in microwave for fifteen hundred seconds at 200° C. The solution was cooled and adjusted to pH 5 with 1N HCl. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic fractions were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 460 (M+H)+; (ESI(−)) m/e 458 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.15 (br s, 1H), 9.54 (s, 1H), 9.02 (br s, 1H), 7.51 (dd, 1H), 7.41 (dt, 1H), 6.96 (2, 1H), 6.86 (d, 1H), 6.64 (m, 2H), 6.00 (t, 1H), 3.29 (q, 2H), 3.09 (m, 7H), 2.65 (br s, 4H), 1.89 (m, 2H), 1.67 (br s, 4H), 1.14 (t, 6H).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[S:29])=[CH:26][CH:25]=1>C(O)(C)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:30]=[C:28]([C:27]3[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[S:29][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC(C)O
Product: COc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccc(S(C)(=O)=O)cc3)s2)cc1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 2-bromo-1- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) ethanone (Example 26, Step 2) (0.500 g, 1.35 mmol) in isopropanol (10 mL) in a 25 mL round bottom flask was added p-methoxythiobenzamide (0.230 g, 1.35 mmol). The solution was heated to reflux for 30 hours and cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and concentrated yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(4-methoxyphenyl)thiazole (0.360 g, 61%) as a crystalline solid: mp 187°-189° C., 1HNMR (CDCl3) 300 mHz 7.99 (d, 8.82 Hz, 2 H), 7.93 (d, J=8.50 Hz, 2 H), 7.63-7.53 (m, 4 H), 7.09 (t, J=8.63 Hz, 2 H), 7.03 (d, J=8.82 Hz, 2 H), 3.92 (s, 3 H), 3.13 (s, 3 H); MS m/z 440 (M+H). HRMS Δ=2.0 mmu.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2([OH:15])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(CC2(O)CCNCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(CC2(O)CCNCC2)cc1
Reaction time: 13 h

Procedure:
6.6 g of Raney nickel is added to a solution of 66.45 g (0.281 mol) of 4-(4-nitrobenzyl)piperidin-4-ol in 660 mL of methanol. The reaction mixture is hydrogenated for 13 hours at ambient temperature and 3 bar hydrogen. The catalyst is filtered off and the filtrate is evaporated down. Yield: 64.5 g (111% of theory); C12H18N2O (M=206.28); calc.: molecular ion peak (M+H)+: 207; found: molecular ion peak (M+H)+: 207.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC(C2C(C3C=CC4C(=CC=C(C5N(C6CCCCC6)C6C=CC(C(NC(CC7C8C(=CC=C(O)C=8)NC=7)C(O)=O)=O)=CC=6N=5)C=4)N=3)=CC(C(N3CCCC3)=O)=CC=2)=CC=1.C[O:99][C:100](=[O:109])[C@H:101]([CH2:103][CH2:104][C:105]([O:107]C)=[O:106])[NH2:102].[OH-].[Na+]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:102][CH:101]([CH2:103][CH2:104][C:105]([OH:107])=[O:106])[C:100]([OH:99])=[O:109])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: O=C(NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCC(NC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1)C(=O)O
Yield: 15 %

Procedure:
Compound 237 was synthesized from Compound 201 as described for Compound 235, using L-glutamic acid dimethylester in place of L-5-hydroxytryptophane. In the 3rd step the protected intermediate was treated with aqueous sodium hydroxide for a 15% yield of the title compound
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:18][C:19](=[O:37])[C@@H:20]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:21]C(OC(C)(C)C)=O)[CH:9]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:18][C:19](=[O:37])[C@@H:20]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH2:21])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)Nc1cnc2ccccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CCc1ccccc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of N-tert-butoxycarbonyl-D-homophenylalanine 3-quinolylamide (A, 114 mg) in dichloromethane (2 mL) at 0° C. After stirring at 0° C. for 5 min and at room temperature for 40 min, the reaction mixture was evaporated and coevaporated three times with toluene and diethyl ether in vacuo to afford the title compound (151 mg) as a pale yellow solid.
Reaction SMILES: Cl.NCC[C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.CC1N=CSC=1C(Cl)=O>Cl.O1CCCC1>[C:8]1([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Agent: Cc1ncsc1C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a mixture of 1.18 g. (0.005 mole) of 4-(2-aminoethyl)-benzenesulfonamide hydrochloride [E. Miller et al., Journal of the American Chemical Society, Vol. 62, p. 2099 (1940)] and 1.4 ml. (0.010 mole) of triethylamine in 15 ml. of dry tetrahydrofuran, there was added 805 mg. (0.005 mole) of 4-methyl-5-thiazolecarboxylic acid chloride dissolved in 15 ml. of tetrahydrofuran. The addition caused a slight exothermic reaction to occur, after which the reaction mixture was allowed to stand at ambient temperatures for a period of approximately 16 hours with constant agitation being maintained throughout the entire step. At this point, the spent mixture was poured into 50 ml. of ice water and subsequently acidified with a few drops of 3N aqueous hydrochloric acid. The resulting cream-colored precipitate was then recovered by means of suction filtration, washed well with cold water and thereafter crystallized from acetonitrile (after treatment with activated carbon) to yield 1.8 g (73%) of pure 4-[2-methyl-5-thiazolecarboxamido)ethyl]benzenesulfonamide, m.p. 182°-183°C.