Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1[C:14](=[O:28])[CH2:15][CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]=1[OH:19])(=O)[CH2:9][CH2:10][CH3:11].Cl.[CH2:30]([O:33][NH2:34])[CH:31]=[CH2:32]>C(O)C>[CH2:30]([O:33][N:34]=[C:8]([C:13]1[C:14](=[O:28])[CH2:15][CH2:16][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]=1[OH:19])[CH2:9][CH2:10][CH3:11])[CH:31]=[CH2:32]
Reactant: CCCC(=O)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Reactant: C=CCON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCON=C(CCC)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Reaction time: 8 h
Yield: 66.6 %

Procedure:
Triethylamine (1.2 g) was added to a solution of 2-butyryl-3-hydroxy-4-(4-methoxyphenyl)cyclohex-2-e-n-1-one (2.9 g) and O-allylhydroxylamine hydrochloride (1.2 g) in absolute ethanol (50 ml) at ambient temperature. After stirring overnight at this temperature, the ethanol was evaporated in vacuo, water was added to the residue and the aqueous solution was extracted with methylene chloride. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was chromatographed on a silica gel column using 10% Et2O--CH2Cl2 as eluant to give the title compound (2.3 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21]3)=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].[F-].[Cs+]>CC#N>[Br:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:21]3[CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[C:39](=[O:40])[C:38]4[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:36]3=[O:45])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1Br
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Yield: 65 %

Procedure:
To a stirred solution of 4 (715 mg, 1.53 mmol), N-(4-bromobutyl)-phthalimide (888 mg, 3.15 mmol) in 20 mL CH3CN, CsF (1.24 g, 8.21 mmol) was added. The resulting mixture was refluxed for 5 hours and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 5 as a yellow amorphous solid (666 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.78-7.65 (m, 6H), 7.58 (s, 1H), 7.48-7.39 (m, 5H), 6.57 (s, 1H), 4.30 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 1.74-1.68 (m, 2H), 1.50-1.46 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.33, 169.95, 168.50, 145.22, 144.25, 136.85, 135.71, 135.07, 134.18, 132.55, 132.15, 132.09, 130.69, 129.52, 128.96, 128.84, 128.74, 123.44, 121.48, 121.42, 120.53, 112.50, 103.12, 61.49, 43.67, 37.26, 35.37, 27.38, 25.81, and 14.44.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1cn(Cc2ccccc2)c2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(Cc3ccccc3)c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as starting compound and 6-bromo-1-(1-benzyl-1 H-indol-3-yl)-1-hexanone were reacted and treated in the same manner as in Example 199 to give 0.43 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-benzyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:18][C:19]1[CH:20]=[C:21]([CH:31]=[C:32]([O:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[CH:33]=1)[C:22]([NH:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1)=[O:23]>C(#N)C>[OH:39][CH2:38][C@@H:35]([O:34][C:32]1[CH:33]=[C:19]([O:18][C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH:20]=[C:21]([C:22]([NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)=[O:23])[CH:31]=1)[CH2:36][CH3:37]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC[C@@H](CO)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 16.3 %

Procedure:
Methyl 5-chloropyrazine-2-carboxylate (104 mg, 0.60 mmol) and cesium carbonate (467 mg, 1.43 mmol) were added to a solution of 3-hydroxy-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (175 mg, 0.570 mmol), in acetonitrile (5 mL) and the mixture heated in a microwave reactor at 160° C. for 330 minutes. The acetonitrile was removed in vacuo and the residue dissolved in ethyl acetate (25 mL), washed with water (20 mL), brine (20 mL), dried (MgSO4) and evaporated to a residue which was chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product (41 mg). 1H NMR δ (CDCl3): 0.97 (t, 3H), 1.78 (quin, 2H), 3.82 (s, 3H), 3.91 (s, 3H), 4.52 (m, 3H), 4.66 (quin, 1H), 6.59 (t, 1H), 6.89 (d, 1H), 7.05 (t, 1H), 7.15 (t, 1H), 8.19 (d, 1H), 8.79 (d, 1H), 9.86 (s, 1H); m/z 442 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:30][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[CH2:24][N:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Nc1ccc(CN2CCCC2)c(Cl)c1
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CN2CCCC2)c(Cl)c1

Procedure:
The product was prepared according to general working method I from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 3-chloro-4-pyrrolidin-1-ylmethyl-phenylamine (140b).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:39]1([CH:45]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:46][C:47]([C:49]2[CH:54]=[CH:53][C:52](O)=[CH:51][CH:50]=2)=[O:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([CH:45]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:46][C:47]([C:49]2[CH:50]=[CH:51][C:52]([O:1][CH2:2][C:3]3[CH2:4][S:5][C@@H:6]4[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:25](=[O:38])[N:7]4[C:8]=3[C:9]([O:11][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:10])=[CH:53][CH:54]=2)=[O:48])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(O)cc1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(C(=O)OC(c4ccccc4)c4ccccc4)cc3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and p-(diphenylmethoxycarbonyl)phenol, to afford 864 mg of the title compound as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:4]=1[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[N:22](S(C3C=CC(C)=CC=3)(=O)=O)[C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:38])[CH:26]=3)=[CH:24][C:17]=12)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8].[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:4]=1[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:38])[CH:26]=3)=[CH:24][C:17]=12)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2cccs2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(CN(Cc2ccnc3[nH]c(-c4cn(C)c5cc(OC)c(OC)cc45)cc23)S(=O)(=O)c2cccs2)c(OC)c1
Yield: 82.9 %

Procedure:
Thiophene-2-sulfonic acid (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is prepared as described in Example 179a starting with 0.150 g of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 1 cm3 of 5N potassium hydroxide. 0.100 g of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is obtained, the characteristics of which are as follows:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[CH:10][C:11](=[O:15])[NH:12][C:13]=1[CH3:14])=[O:7].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>O1CCOCC1>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:14][C:13]1[NH:12][C:11](=[O:15])[CH:10]=[CH:9][C:8]=1[C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: COC(OC)N(C)C
Reactant: Cc1[nH]c(=O)ccc1C(=O)c1ccco1
Solvent: C1COCCO1
Product: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccco1

Procedure:
C-1. 6-[2-(Dimethylamino)ethenyl]-5-(2-furanylcarbonyl)-2(1H)-pyridinone--A mixture containing 30.5 g of 5-(2-furanylcarbonyl)-6-methyl-2(1H)-pyridinone, 400 ml of p-dioxane and 25 ml of dimethylformamide dimethyl acetal was heated under reflux for 6 hours and then allowed to cool. The separated crystalline product was collected, washed with isopropyl alcohol and dried in a vacuum oven at 80°-85° C. to yield 28.4 g of 6-[2-(dimethylamino)ethenyl]-5-(2-furanylcarbonyl)-2(1H)-pyridinone, m.p. 238°-240° C. with decomposition. The mother liquor on concentration yielded another 5.6 g of product.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:23])[N:5]([C:11]2[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[C:14]([Cl:21])=[CH:13][C:12]=2[F:22])[C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2].S(OC)(O[CH3:28])(=O)=O>>[CH2:1]([C:3]1[C:4](=[O:23])[N:5]([C:11]2[CH:16]=[C:15]([O:17][CH:18]([CH3:19])[CH3:20])[C:14]([Cl:21])=[CH:13][C:12]=2[F:22])[C:6](=[O:10])[N:7]([CH3:28])[C:8]=1[CH3:9])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCc1c(C)[nH]c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Product: CCc1c(C)n(C)c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using 5-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-methyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 5-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,6-dimethyl-2,4(1H,3H)-pyrimidinedione, m.p. 124°-125° C.;
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH:41]([Mg]Br)=[CH2:42]>C1COCC1>[OH:16][C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:14]=[CH:13]2)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH2:41][CH3:42]
Reactant: C=C[Mg]Br
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2cc(C(=O)NC)ccc2c1)c1c[nH]cn1

Procedure:
The similar reaction as described in Example 50-(i) was carried out by using N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (700 mg) and vinylmagnesium bromide in THF (1M; 5 mL) to give the titled compound (478 mg) as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH2:11].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](N1C=CN=C1)=[S:20].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)=[S:20]
Reactant: NCCc1c(F)cccc1F
Reactant: S=C(Nc1ccccn1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1CCNC(=S)Nc1ccccn1
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A solution of 2-(2,6-difluorophenyl)ethylamine (0.43 g, 2.7 mmol) and 1-[(2-pyridyl)thiocarbamoyl] imidazole (0.55 g, 2.7 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 27 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.08 g (10%) of the titled product as a pale yellow solid:
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][CH2:8][N:9]([CH3:52])[S:10]([C:13]1[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=1)[C:16]([NH:18][C:19]1[S:20][C:21]2[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=2[C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)=[O:25])=[O:17])(=[O:12])=[O:11])(C)(C)C.FC(F)(F)C(O)=O.ClCCl.[OH-].[Na+]>C(O)C>[C:6]([CH2:7][CH2:8][N:9]([CH3:52])[S:10]([C:13]1[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=1)[C:16]([NH:18][C:19]1[S:20][C:21]2[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=2[C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=2)=[CH:29][CH:28]=1)=[O:25])=[O:17])(=[O:12])=[O:11])([OH:53])=[O:5]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)CCC(=O)OC(C)(C)C)c4)sc4c3CCCC4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CN(CCC(=O)O)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
A mixture of 200 mg of methyl 4-{2-[4-({[2-({3-[(3-tert-butoxy-3-oxopropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 2.0 mL of trifluoroacetic acid, and 2.0 mL of dichloromethane was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and to the obtained crude product were added 0.50 mL of a 5.0 M aqueous sodium hydroxide solution and 2.0 mL of ethanol, followed by heating and refluxing overnight. The reaction mixture was concentrated under reduced pressure and to the obtained residue were added water and citric acid (500 mg), followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol). The crude product was washed with ethyl acetate to obtain 135 mg of 4-{2-[4-({[2-({3-[(2-carboxyethyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid as a colorless crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:40])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][CH2:37][N:38]=2)=[CH:25][CH:24]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:40])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:38][CH2:37][CH2:36][CH2:35][N:34]=2)=[CH:25][CH:24]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCCN1

Procedure:
87 mg of the tert-butyl ester obtained in step d) were stirred at room temperature for 15 min in 2 ml of 95% strength trifluoroacetic acid. After concentrating in vacuo, the mixture was triturated with ether, and the residue was filtered off and dried. Yield: 79 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[CH3:17][CH:18]([OH:21])[C:19]#[CH:20].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[CH:7]=[C:2]([O:21][CH:18]([CH3:17])[C:19]#[CH:20])[N:3]=1
Reactant: C#CC(C)O
Reactant: Cc1nc(Cl)cc(-c2cccc(F)c2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)Oc1cc(-c2cccc(F)c2F)nc(C)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 86 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 255 mg of 4-chloro-2-methyl-6-(2,3-difluorophenyl)pyrimidine and 97 mg of 3-butyn-2-ol, to which 56 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 250 mg of 2-methyl-4-(2,3-difluorophenyl)-6-(1-methyl-2-propynyloxy)pyrimidine (the present compound (161)).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]=1[OH:24]>O1CCCC1>[CH2:17]([O:16][C:14]1[CH:13]=[CH:12][C:11]([OH:24])=[C:10]([CH2:9][OH:8])[CH:15]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(OCc2ccccc2)ccc1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Lithium aluminium hydride (0.235 g, 6.2 mMol) was suspended in tetrahydrofuran (25 ml) and cooled to 0° C. 5-Benzyloxy-2-hydroxy benzoic acid methyl ester (2 g, 7.75 mMol) in tetrahydrofuran (10 ml) was added dropwise, via cannula. The mixture was warmed to room temperature and stirred for 20 minutes. The reaction was then cooled to 0° C. and cautiously quenched by the addition of water (0.5 ml), 2M sodium hydroxide solution (0.5 ml), and water (1 ml). The resulting mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was evaporated in vacuo to yield 4-benzyloxy-2-hydroxymethyl phenol as a clear oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Fc1ccccc1I
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccccc4F)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-2-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 470.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][C@@H:10]([NH:12][C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH3:11])C1C=CC=CC=1.Cl>C(O)C.[Pd]>[CH3:1][NH:8][CH2:9][C@@H:10]([NH:12][C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH3:11]
Reactant: COC(=O)[C@H](C)N[C@@H](C)CN(C)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC[C@H](C)N[C@@H](C)C(=O)OC
Reaction time: 16.75 h

Procedure:
(S)-Methyl 2-((S)-1-(benzyl(methyl)-amino)propan-2-ylamino)-propanoate (0.98 g, 3.7 mmol), concentrated HCl (mL) and 10% Pd on carbon (200 mg) were combined in ethanol (25 mL). The reaction mixture was shaken on a Parr apparatus under a hydrogen atmosphere (15 psi). After 16.75 h, the reaction mixture was filtered through Celite and the Celite pad was rinsed with CH3OH and CH2Cl2. The filtrate was concentrated under reduced pressure to give (S)-methyl 2-((S)-1-(methylamino)propan-2-ylamino)propanoate which was used directly in the next reaction. MS consistent.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C@H:33]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1.[CH3:60][O:61][C:62]1[CH:63]=[C:64](O)[CH:65]=[CH:66][C:67]=1[O:68][CH3:69]>C1COCC1>[CH3:60][O:61][C:62]1[CH:63]=[C:64]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[O:32][C@@H:33]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51])[CH:45]=[CH:46][CH:47]=2)[CH2:38][CH2:37]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: COc1ccc(O)cc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(O[C@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
Into a 25-mL RB-flask was added triphenylphosphine (9.80 mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol), N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3,4-dimethoxyphenol (7.70 mg, 0.050 mmol) and THF (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (16 hrs). The solvent was removed under reduced pressure and the residue was purified by preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] to afford the desired product (4.4 mg, 34.1% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ7.46 (s, 1H), 7.40–7.30 (m, 4H) 7.25 (m, 3H), 6.97 (d, 1H, J=7.8 Hz), 6.64 (d, 1H, J=9.1 Hz), 6.51 (d, 1H, J=2.6 Hz), 6.29 (d, 1H, J=2.6, 9.1 Hz), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.80 (s, 3H), 3.77 (s, 3H), 3.23 (m, 2H), 2.77 (m, 2H), 2.5 (m, 2H), 2.3–2.1 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 517.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of 4-bromo-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.21 (d, 1H, J=2.4 Hz), 7.49-7.61 (m, 5H), 7.73 (d, 1H, J=8.8 Hz), 8.86 (dd, 2H, J=4.4 Hz, 1.2 Hz), 10.00 (s, 1H). MS: m/z 451.9 (M++1)