Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH:8]12[CH2:17][CH:12]([CH2:13][C:14](=[O:16])[CH2:15]1)[CH2:11][C:10](=[O:18])[CH2:9]2.[NH4+].[Cl-].C(Cl)Cl>Cl.C1COCC1.[Zn]>[OH:18][C:10]12[CH2:11][CH:12]3[CH2:17][CH:8]([CH2:15][C:14]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])([CH2:13]3)[O:16]1)[CH2:9]2
Reactant: O=C1CC2CC(=O)CC(C1)C2
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)CC12CC3CC(CC(O)(C3)O1)C2

Procedure:
Zn solid was activated just prior to perform Reformatsky reaction as followed: Zn dust was stirred at r.t. in 2 M aqueous HCl solution until the bubbling ceased (≈40 min for 15 g Zn). The solid was then filtered and washed with water (50 mL), the EtOH (50 mL), acetone (50 mL), then Et2O (50 mL) and the thin solid was heated using an air gun under vacuum to complete drying. Reformasky reaction: to a suspension of such activated Zn* solid (2.29 g, 35 mmol) in dry THF (70 mL) warmed to reflux temperature under argon was added dropwise through the condenser over 40 min a mixture of ethylbromoacetate (1.75 mL, 15 mmol) and diketone (1) (0.761 g, 5 mmol) in dry THF (125 mL). The green mixture was stirred at reflux temperature for 5 h, then cooled to r.t. and hydrolyzed by quite slow addition of saturated aqueous NH4Cl solution (until pH=5-6): the resulting colorless solution with the Zn solid floating around was stirred for 10 min at r.t. before extraction with DCM (3×80 mL). The combined org. layers were washed with saturated solution of NaHCO3 (80 mL), then brine (80 mL), then water (80 mL), dried with MgSO4 and concentrated under reduced pressure to afford an orange oil. This crude product was then filtered trough a plug of silica gel and washed with AcOEt/cyclohexane mixtures, then with pure AcOEt to afford the desired acetal (2) as yellow oil pure enough to carry on the synthesis. A purer product can be obtained as white crystals (1.044 g, 87%) after flash chromatography (AcOEt/cyclohexane 4/6, v/v).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:33]([O:35][CH:36]([O:43][CH2:44][CH3:45])[C:37]#[C:38][C:39]([O:41][CH3:42])=[O:40])[CH3:34]>C1COCC1.O>[CH2:44]([O:43][CH:36]([O:35][CH2:33][CH3:34])/[C:37](/[O:12][C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:11][CH:10]=1)=[CH:38]/[C:39]([O:41][CH3:42])=[O:40])[CH3:45]
Reactant: Oc1ccc(C2CCCC2)cc1
Reactant: CCOC(C#CC(=O)OC)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)/C(=C/C(=O)OC)Oc1ccc(C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a solution of 2.42 g (15 mmol) of 4-cyclopentylphenol in 50 mL of THF was added 1.12 g (20 mmol) of powdered KOH and 5.28 g (20 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 3.73 g (20 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetate-hexane yielded 2.01 g (58%) of an oil, used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][NH2:10])=[N:6][N:5]=[N:4]1)[CH3:2].C(I)C.BrCC[CH2:17][OH:18]>>[NH2:10][CH2:9][CH2:8][C:7]1[N:3]([CH2:1][CH2:2][CH2:17][OH:18])[N:4]=[N:5][N:6]=1
Reactant: OCCCBr
Reactant: CCn1nnnc1CCN
Solvent: CCI
Product: NCCc1nnnn1CCCO

Procedure:
This material is prepared by an analogous procedure to intermediate CI2 by replacing the ethyliodide in step 1 with 3-bromo-1-propanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:20][CH:21]=[CH2:22])[CH2:14][C:15]([O:17]CC)=O)[CH3:9])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:20]([C@:13]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:12][CH2:11][N:10]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:9])[C:15](=[O:17])[CH2:14]1)[CH:21]=[CH2:22]
Reactant: C=CCC(CCN[C@@H](C)c1ccc(Br)cc1)(CC(=O)OCC)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1

Procedure:
To a solution of ethyl 3-(2-((S)-1-(4-bromophenyl)ethylamino)ethyl)-3-phenylhex-5-enoate (4.6 g, 9.1 mmol) in anhydrous toluene (80 mL) was heated to reflux for 2 days. The reaction was concentrated to give the crude (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-phenylpiperidin-2-one. The residue was purified by column chromatography to give the final product (1.2 g, 33%). 1H NMR (CDCl3): δ 1.13 (m, 3H), 1.76 (m, 1H), 1.97 (m, 1H), 2.24 (m, 1H), 2.43 (m, 2H), 2.57 (m, 2H), 2.94 (m, 1H), 4.89 (m, 2H), 5.35 (m, 1H), 6.01 (m, 1H), 7.03 (m, 2H), 7.21 (m, 3H), 7.30 (m, 2H), 7.42 (m, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[N:17]=[C:16]([CH2:18][CH2:19][CH:20]=[O:21])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(CCCO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cccc(CCC=O)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A solution of DMSO (1.78 g, 22.9 mmol) in dichloromethane (4mL) was added dropwise over 3 min into solution of oxalyl chloride (11.3 mmol) in dichloromethane (6 mL) cooled to -78° C. under nitrogen. The reaction mixture was stirred for 5 min when 3-(6-methyl-2-pyridyl)propanol (1.57 g, 10.4 mmol) in dichloromethane (20 mL) was added over 5 min. The stirring continued for 20 min at -78° C. and triethylamine (8 ml) was added resulting in dark slurry. The cooling bath was removed and after 3 hr, the reaction mixture was quenched with brine followed by dichloromethane extraction (3×). After solvent removal, the dark residue was purified by column chromatography (silica gel, ethyl acetate) yielding a yellow oil (77%). MS (DCI) (M+H)+ at m/z 150.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C1COCC1.CCCCCC>[F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a stirred solution of 5,5,5-trifluoropentanoic acid (5 g, 32.0 mmol) in THF (30 mL) and hexane (30 mL) at 0° C., was added tert-butyl 2,2,2-trichloroacetimidate (11.46 mL, 64.1 mmol). The mixture was stirred for 15 min at 0° C. Boron trifluoride etherate (0.406 mL, 3.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. To the clear reaction mixture was added solid NaHCO3 (5 g) and stirred for 30 min. The mixture was filtered through MgSO4 and washed with hexanes (200 mL). The solution was allowed to rest for 45 min, and the resulting solid material was removed by filtering on the same MgSO4 filter again, washed with hexanes (100 mL) and concentrated under reduced pressure without heat. The volume was reduced to about 30 mL, filtered through a clean fritted funnel, washed with hexane (5 mL), and then concentrated under reduced pressure without heat. The resulting neat oil was filtered through a 0.45 μm nylon membrane filter disk to provide Intermediate S-1G (6.6 g, 31.4 mmol 98% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (s, 9 H) 1.74-1.83 (m, 2 H) 2.00-2.13 (m, 2 H) 2.24 (t, J=7.28 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2cc(-c3ccccc3C)sc2c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1-c1cc2cc(O)c(Cl)c(Cl)c2s1
Yield: 73.2 %

Procedure:
A mixture of 4.0 g of 6,7-dichloro-5-methoxy-2-(2'-methylphenyl)benzo[b]thiophene and 40 g of pyridine hydrochloride is heated at 200°-205° for 3 hrs. To the cooled mixture is added 250 ml of water and the aqueous mixture is extracted with three 200 ml-portions of ethyl ether. The organic layers are combined, washed dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the residue from ether-pentane gives 2.8 g of 6,7-dichloro-5-hydroxy-2-(2'-methylphenyl)benzo[b]thiophene, mp 106°-107°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([N+:9]([O-])=O)[CH:3]=1.[SH:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.CC1C=CC(O)=C([N+]([O-])=O)C=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([NH2:9])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: Oc1ccc(S)cc1
Agent: Cc1ccc(O)c([N+](=O)[O-])c1
Product: Nc1cc(F)ccc1Sc1ccccc1

Procedure:
4-Fluoro-2-nitrophenol was reacted according to procedures similar to those described in Examples 6a, 6b, and 6c substituting benzenethiol for 4-mercaptophenol and 4-fluoro-2-nitrophenol for 4-methyl-2-nitro phenol to provide the title compound.
Reaction SMILES: [C:1]1(=O)[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.C([Li])CCC.CCCCCC.[NH4+].[Cl-]>C(O)(C)C>[CH2:7]1[C:6]2[C:10](=[CH:11][C:12]3[CH2:1][CH:2]=[CH:3][C:4]=3[CH:5]=2)[CH2:9][CH2:8]1
Reactant: O=C1CCc2cc3c(cc21)CCC3
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)O
Product: C1=Cc2cc3c(cc2C1)CCC3
Temperature: 25 °C

Procedure:
The mixture of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one (12.4 g, 0.072 mol), p-toluenesulfonyl hydrazide (13.4 g, 0.072 mol), 0.5 g TSA and i-propanol (100 ml) was refluxed by 5 min, and cooled to room temperature. Precipitate was filtered, washed by MeOH and dried, given 21 g of product (90%). Suspension of obtained hydrazone in 250 ml abs. Et2O was cooled to −70° C. and was treated with 15% n-butyllithium in hexane (100 ml. 0.16 mol). The resulting mixture was allowed to warm up to r.t. and refluxed until gas evolution. Reaction mixture was treated with 50 ml NH4Cl (10%), washed by water and dried. Solvent was evaporated, the residue was extracted by hot hexane, and to give after evaporation 9.1 g of solid product (81%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH3:11].P(Br)(Br)[Br:14]>>[Br:14][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH3:11]
Reactant: BrP(Br)Br
Reactant: CCC(O)c1cccc(F)c1F
Product: CCC(Br)c1cccc(F)c1F

Procedure:
rac-1-(1-Bromo-propyl)-2,3-difluoro-benzene was prepared from rac-1-(2,3-Difluoro-phenyl)-propan-1-ol and phosphorus tribromide in analogy to Example 23 b): colourless oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>CC(=O)CC.[I-].[Li+]>[CH2:26]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:25][CH:24]=[CH2:23]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: C=CCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 92.5 %

Procedure:
To a solution of di-tert-butyliminodicarboxylate (868 mg, 4 mmol), cesium carbonate (2.61 g, 8 mmol), and lithium iodide (28 mg, 0.2 mmol) in 2-butanone (20 mL) was added 4-bromobutene (812 mg, 6 mmol) and the mixture was heated at reflux for 48 h. The reaction was allowed to cool and was quenched with brine (40 mL) and extracted with diethyl ether (3×20 mL). The combined organic fractions were washed with brine (30 mL), dried, and evaporated to yield the title compound (1.01 g, 3.7 mmol, 93%) as a light brown oil. 1H NMR (CDCl3, 300 MHz): δ 5.77 (m, 1H, H3); 5.04 (m, 2H, H4); 3.62 (dd, J=6.0, 8.7 Hz, 2H, H1); 2.30 (m, 2H, H2); 1.51 (s, 18H, 2×(CH3)3). Mass Spectrum (ES, +ve) m/z 310 (55%) [MK+]1, 294 (30%) [MNa+], 272 (40%) [MH+]. HRMS calcd for C14H26NO4 272.1862, found 272.1848.
Reaction SMILES: [N:1]([C@@H:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:5]([O:10]CC1C=CC=CC=1)[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-].[CH3:24][OH:25]>[Pd]>[CH3:9][O:8][C:6](=[O:7])[C@H:5]([OH:10])[C@H:4]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:1][C:24](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CO
Reactant: COC(=O)[C@H](OCc1ccccc1)[C@@H](N=[N+]=[N-])c1ccccc1
Agent: [Pd]
Product: COC(=O)[C@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 74 %

Procedure:
The azide 10 (10 g, 24 mmol) was hydrogenated with 10% Pd/C (2.5 g) in methanol under H2 (50 p.s.i.) for 4 h. The solution was filtered, stood at 23° C. for 48 h, and concentrated. The solid was recrystallized over chloroform-methanol (50:1) to give 16 (5.5 g, 74%):[a]D20=-49 (c 1, CH3OH), lit. [a]D20=-49.6° (c 1, CH3OH); 1H NMR (CD3OD) d 3.68 (s, 3H), 4.60 (d, J=3.8 Hz, 1 H), 5.58 (d, J 3.8 Hz, 1 H), 7.32-7.61 (m, 8 H), 7.98-8.11 (m, 2 H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8]([CH2:11][NH:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]=O.[OH-].[Na+]>O1CCOCC1>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]([CH2:11][N:12]([CH3:24])[CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CC=C(CNCc2cccc3ccccc23)CC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(CC1=CCC(C(C)(C)C)CC1)Cc1cccc2ccccc12

Procedure:
0.8 g of N-(4-tert.butyl-1-cyclohexenylmethyl)-1-naphthylmethylamine are reacted with 13 ml of 1N NaH2PO3 -solution and brought into solution by the addition of 15 ml of dioxane. Following addition of 1.1 ml 37% formaline solution the mixture is warmed to 60° for 1/2 hour, made alkaline with caustic soda and extracted with ether. Following drying and evaporation of the organic phase the pure product is obtained as an oil.
Reaction SMILES: CON(C)[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[CH3:34][C:35]([CH3:39])=[CH:36][Mg]Br>C1COCC1>[CH3:34][C:35]([CH3:39])=[CH:36][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1)=[O:32]
Reactant: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Reactant: CC(C)=C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)=CC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (50 mg, 0.11 mmol) in THF (0.5 mL) at 0° C. was added 2-methylpropenylmagnesium bromide (1.1 mL, 0.55 mmol, 0.5 M in THF). The reaction mixture was allowed to stir at room temperature for 30 min. It was quenched with sat. NH4Cl solution (0.5 mL) and was extracted with EtOAc (3×2 mL). The combined organic layer was washed with brine, was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure to give a white solid, which was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give 3-methyl-1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)but-2-en-1-one (I-87) as an off white solid. 1H NMR (CDCl3) δ ppm: 2.01 (s, 3H), 2.20 (s, 3H), 6.14 (s, 1H), 6.71 (s, 1H), 6.95 (s, 1H), 6.99-7.02 (m, 5H), 7.11 (t, J=7.36 Hz, 1H), 7.26-7.28 (m, 2H), 7.34 (t, J=7.56 Hz, 2H), 7.40-7.53 (m, 2H), 7.65 (d, J=7 Hz, 1H), 7.86 (s, 1H), 8.32 (s, 1H); LCMS: m/e 437.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:23][CH:22]=[CH:21][N:20]=2)(=[O:16])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccc(Cl)s1
Reactant: OCc1ccccn1
Product: O=S(=O)(Nc1nccnc1OCc1ccccn1)c1ccc(Cl)s1
Temperature: 70 °C

Procedure:
Prepared by the method of Example 20b using pyridine-2-methanol and 5-chloro-N-(3-chloro-2-pyrazinyl)-2-thiophenesulphonamide with reaction mixture heated at 70° C. for 4 h.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([CH2:18][C:19](=O)[CH3:20])[N:11]=1.Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1.C(OCC)(=O)C>[Cl-].[Zn+2].[Cl-].O>[Cl:23][C:24]1[CH:29]=[C:28]2[C:27](=[CH:26][CH:25]=1)[NH:30][C:19]([CH3:20])=[C:18]2[C:12]1[N:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]([O:9][CH3:8])[N:11]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(-c2c(C)[nH]c3ccc(Cl)cc23)n1
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To 80 ml of toluene were added 8.0 g (40 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone and 7.9 g (44 m moles) of 4-chlorophenylhydrazine hydrochloride. Thereto was added 6.54 g (48 m moles) of zinc chloride. Refluxing was made for 2 hours with heating. The reaction mixture was allowed to cool. Then, ethyl acetate and water were added to dissolve the whole reaction mixture. The organic layer was washed with water, separated, and dried over Glauber's salt. The resulting organic layer was concentrated under reduced pressure using a rotary evaporator to obtain an orange solid. The solid was washed with isopropyl ether to obtain 10.2 g (33.7 m moles) of 5-chloro-3-(4,6-dimethoxypyrimidine-2-yl)-2-methylindole. Yield: 84% Melting point: 179 to 181° C.
Reaction SMILES: FC(F)(F)C(O)=O.[OH-].[K+].[F:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:14]([CH:16](C(OCC)=O)[C:17]([O:19][C:20](C)(C)[CH3:21])=[O:18])=[O:15]>>[F:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OC(C)(C)C)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CC(=O)OCC)cc1F
Reaction time: 3 h

Procedure:
A solution of 3.0 g. of tert-butyl ethyl 3-fluoro-4-(hexadecylamino)benzoylmalonate 10 ml of trifluoroacetic acid is warmed with stirring for 3 hours. The solution is poured onto ice and neutralized with potassium hydroxide. The resulting precipitate is collected by filtration, washed with water and dried. Recrystallization from chloroform affords ethyl 3-fluoro-4-(hexadecylamino)benzoylacetate.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[Na].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26](Cl)[N:21]2[N:20]=1)(=[O:18])=[O:17].Cl>CO.C(Cl)Cl.CO>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26]([O:2][CH3:1])[N:21]2[N:20]=1)(=[O:18])=[O:17]
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Reaction time: 0.17 h

Procedure:
A sodium methoxide-methanol solution was made by dissolving 0.3 g (13 mg-atom) of sodium metal into 20 ml of absolute methanol. To this solution was added 1.0 g (2.5 mmol) of N-(2,6-dichlorophenyl)-7-chloro-5-methyl-1,2,4-triazolo-[1,5-a]pyrimidine-2-sulfonamide. A mild exotherm ensued and the reaction was complete within 10 min as determined by TLC (20 percent methanol-methylene chloride). The solution was acidified with 6N aqueous HCl and the resulting white solid collected. Recovered 0.9 g (93 percent) of a white powder; mp 214°-215° C.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][CH2:11][CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.C1(=O)N([O:23][C:24](=O)[C@H:25]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])C(=O)CC1.CN(C)C=O>O>[C:30]([O:29][C:27]([NH:26][C@H:25]([C:24]([NH:10][CH2:11][CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:23])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28])([CH3:32])([CH3:33])[CH3:31]
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
Triethylamine (3.5 ml) is added to a mixture of histamine dihydrochloride (1.84 g), N-tert-butoxycarbonyl-L-phenylalanine succinimido ester (3.62 g), dimethylformamide (20 ml) and water (5 ml) under ice-cooling and then the mixture is stirred at room temperature for three hours. The reaction mixture is concentrated under reduced pressure to remove solvent and ethyl acetate is added to the residue and then, insoluble materials are filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution and water, dried, and then concentrated to remove solvent. The residue is crystallized with ether to give N-(N-tert-butoxycarbonyl-L-phenylalanyl)histamine (2.5 g). The product (1.79 g) thus obtained is dissolved in 15% hydrogenbromide-acetic acid solution and the solution is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure to give N-(L-phenylalanyl) histamine dihydrobromide (2.1 g). The thus-obtained product (2.1 g) is dissolved in dimethylformamide, and N-tert-butoxycarbonyl-L-phenylalanine succinimido ester (1.81 g) and triethylamine (2.1 ml) are added thereto and then the mixture is stirred overnight. Ethyl acetate is added to the reaction mixture, and insoluble materials are filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution and dried, and then concentrated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=9:1) and crystallized with ether to give N-(N-tert-butoxycarbonyl-L-phenylalanyl L-phenylalanyl)histamine (1.88 g) as white crystals. Yield ; 74.3%