Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]I)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[C:9]2=[O:35])=[CH:4][CH:3]=1.[CH3:36][NH:37][CH2:38][CH2:39][S:40]([OH:43])(=[O:42])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:35])[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[CH:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:37]([CH3:36])[CH2:38][CH2:39][S:40]([OH:43])(=[O:42])=[O:41])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCI)cc2)N1c1ccc(F)cc1
Reactant: CNCCS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(CCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CCS(=O)(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
64.5 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(4 iodobutoxy)phenyl]azetidin-2-one are dissolved in 3 ml of methanol. 60.7 mg of 2-methylaminoethanesulfonic acid are then dissolved in 1 ml of water, and 30.4 mg of potassium carbonate are added. The reaction solution is stirred at 50° C. for 8 h. After concentration using a rotary evaporator at 40° C., the residue is passed over a reverse-phase cartridge (methanol). The resulting crude product is dissolved in hot methanol. The precipitate formed on cooling is filtered off, and the mother liquor is concentrated using a rotary evaporator. The product is obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=O)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.P(Cl)(Cl)(Cl)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:18])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: NC(=O)c1cnn2c(-c3cccnc3)ccnc12
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 1.0 g. of 7-(3-pyridyl)pyrazolo[1,5-a]-pyrimidine-3-carboxamide and 5 ml. of phosphorus oxychloride is heated at reflux temperature for 3 hours. The mixture is concentrated to dryness in vacuo. The residue is dissolved in dichloromethane and washed with a saturated solution of sodium bicarbonate. The dichloromethane solution is dried over magnesium sulfate and passed through a column of hydrous magnesium silicate. The eluent is concentrated and diluted with hexane to give the product of the example as crystals, m.p. 258°-260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.C([O:13][C:14]([C:16]1[CH:29]=[C:19]2[C:20](=[O:28])[N:21](CC3CC3)[CH2:22][CH2:23][N:18]2[N:17]=1)=O)C.C1(CN2CCN3N=C(CO)C=C3C2=O)CC1>>[OH:13][CH2:14][C:16]1[CH:29]=[C:19]2[C:20](=[O:28])[N:21]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:22][CH2:23][N:18]2[N:17]=1
Reactant: CCOC(=O)c1cc2n(n1)CCN(CC1CC1)C2=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C1c2cc(CO)nn2CCN1CC1CC1
Product: COc1ccc(CN2CCn3nc(CO)cc3C2=O)cc1

Procedure:
The compound was prepared from 1-(3-tert-butoxycarbonylaminoethyl)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester and 4-methoxybenzyl chloride using the methods described in the preceding examples 49 (5-cyclopropylmethyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester) and 50 (5-cyclopropylmethyl-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C.[F:27][C:28]([F:48])([F:47])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:37]2=[O:46])=[CH:32][CH:31]=1.[C:49]([O:53][CH2:54][C:55](O)=[O:56])([CH3:52])([CH3:51])[CH3:50]>>[C:49]([O:53][CH2:54][C:55]([N:43]1[CH2:42][CH2:41][C:38]2([C:37](=[O:46])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][C:28]([F:27])([F:47])[F:48])=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)[CH2:45][CH2:44]1)=[O:56])([CH3:52])([CH3:51])[CH3:50]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CC(C)(C)OCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: CC(C)(C)OCC(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 13 step A (using TBTU instead of BOP as the coupling reagent) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and tert-butoxy-acetic acid. White solid. MS (ESI): 429.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1.N>>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)[CH:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1cccc(Cl)c1
Agent: N
Product: Clc1cncc(-c2cc(-c3cccc(Cl)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.61-7.68 (m, 2H), 7.85-7.89 (m, 1H), 7.90 (s, 1H), 7.96-8.00 (m, 1H), 8.43 (t, J=2.1 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 9.08 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:16])=[C:5]([C:12]([F:15])([F:14])[F:13])[C:6]=1[C:7]([O:9]CC)=O.[CH2:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[S:3][C:4]([CH3:16])=[C:5]([C:12]([F:13])([F:14])[F:15])[C:6]=2[CH2:7][OH:9])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCOC(=O)c1c(Br)sc(C)c1C(F)(F)F
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2sc(C)c(C(F)(F)F)c2CO)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 220 by Suzuki coupling of ethyl 2-bromo-5-methyl-4-(trifluoromethyl)thiophene-3-carboxylate and 4-ethyl-phenylboronic acid followed by synthetic steps to afford the desired product as a yellow oil.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15]CC)=O)[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:15])[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Aqueous NaOH (1.11 g, 27.88 mmol) was added to a solution of ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (5 g, 18.58 mmol) in EtOH (50 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Solid obtained was filtered and dried under reduced pressure to obtain corresponding acid. The crude acid (4.4 g, 18.2 mmol) was then dissolved in DMSO (20 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (5.55 g, 36.51 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (14.24 g, 27.38 mmol) was added to it and stirring was continued overnight. After completion of the reaction, reaction mass was poured into ice to obtain a solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (4 g, 58.5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C.CC(O)C>O>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: NCc1ccccn1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.1 %

Procedure:
A mixture of 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (0.82 g, 2.92 mmol), 2-(aminomethyl)pyridine (0.35 g, 3.21 mmol), triethylamine (0.32 g, 0.45 ml, 3.21 mmol) and propan-2-ol (20 ml) was stirred at ambient temperature for 72 hours. Water (50 ml) was added to the reaction mixture and the organic phase was extracted using dichloromethane (3×50 ml). The combined extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give 2-chloro-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (1.0 g) as a white solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[NH2:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(Cl)ccc1N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
7 g (20 mmol) of 2-amino-5-chlorotoluene were dissolved in 10 ml of sulfuric acid at 10° C. to form a reactant solution. 2.05 ml fuming nitric acid were dissolved in 10 ml concentrated sulfuric acid and the resultant acidic solution was added slowly dropwise to the reactant solution. The reactant solution was then stirred for 3 to 4 hours at room temperature and subsequently added to ice. The yellow product crystals were filtered with suction and recrystallized from methanol. 6.4 g (70% of the theoretical yield) of 2-amino-5-chloro-4-nitrotoluene, which melted at 115° C., were obtained.
Reaction SMILES: Br[C:2]1[C:3]([O:16][C:17]2[N:25]=[C:24]3[C:20]([N:21]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[CH:22]=[N:23]3)=[CH:19][N:18]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:38]1([N:41]2[CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=[N:42]2)[CH2:40][CH2:39]1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:38]1([N:41]2[CH:45]=[C:44]([C:2]3[C:3]([O:16][C:17]4[N:25]=[C:24]5[C:20]([N:21]([CH:26]6[CH2:31][CH2:30][CH2:29][CH2:28][O:27]6)[CH:22]=[N:23]5)=[CH:19][N:18]=4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]4)[CH:43]=[N:42]2)[CH2:40][CH2:39]1
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ncc4c(ncn4C4CCCCO4)n3)c2CC[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3ncc4c(ncn4C4CCCCO4)n3)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A 100-mL, round-bottom flask was charged with 1-((S)-6-bromo-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.200 g, 0.41 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.030 g, 0.04 mmol), potassium carbonate (0.170 g, 1.23 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.288 g, 1.23 mmol), 1,4-dioxane (20 mL), and water (2 mL). The resulting mixture stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was passed through a short pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1:2, ethyl acetate/petroleum ether) to afford 1-((S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(7-(tetrahydro-2H-pyran-2-yl)-7H-purin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.150 g, 71%) as light yellow oil. MS (ESI, pos. ion) m/z 514 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>C1COCC1>[CH3:13][O:12][C:8](=[O:11])[CH2:9][CH2:10][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CCNC1CCCCC1
Yield: 73.5 %

Procedure:
Cyclohexylamine (Aldrich; 17 g, 0.174 mol) was dissolved in THF (300 mL). To this was added methyl acrylate (Aldrich; 15 g, 0.174 mol) in one portion. The reaction mixture was stirred over the weekend. The solvent was evaporated with care due to the volatility of the product and the residue distilled at 72° C. at 0.30 mbar to yield the title compound as a clear oil (23.7 g, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:45]([O:47][CH:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[C:9]([NH:11][C@@H:12]2[C:43](=[O:44])[N:14]3[C:15]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH3:26])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:4][CH:3]=1.C[O-].[Li+].[Cl:64]OC(C)(C)C.C(O)(=O)C>O1CCCC1.CO.C(OCC)(=O)C>[Cl:64][C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([C:45]([O:47][CH:48]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])[C:9]([NH:11][C@@H:12]1[C:43](=[O:44])[N:14]2[C:15]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:28])=[C:16]([CH2:19][S:20][C:21]3[N:25]([CH3:26])[N:24]=[N:23][N:22]=3)[CH2:17][S:18][C@H:13]12)=[O:10]
Reactant: CC(C)(C)OCl
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccc(O)cc3)[C@H]2SC1
Agent: C[O-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(Cl)(C(=O)OC(c3ccccc3)c3ccccc3)c3ccc(O)cc3)[C@H]2SC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diphenylmethyl 7β-(α-p-hydroxyphenyl-α-diphenylmethoxycarbonylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (310 mg) in tetrahydrofuran (15 ml) are added 2 M lithium methoxide in methanol (0.63 ml) and after 1 minute t-butyl hypochlorite (42.6 μl) at -78° C., and the mixture is stirred at -78° C. for 15 minutes. The reaction mixture is mixed with acetic acid (0.3 ml), warmed to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate, and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel (30 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (9:1) to give diphenylmethyl 7β-(α-chloro-α-p-hydroxyphenyl-α-diphenylmethoxycarbonylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (206 mg) NMR: δCDCl3 5.74dd(4.5;9 Hz)1H, together with the following 7α-methoxy compound.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)([OH:3])=O.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:37]([NH:44][C:1]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:10][CH:11]=1)=[O:3])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)NCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(ee) Saponification of tert-butyl (3RS,4RS)-4-(4-ethoxycarbonyl-methoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 86 (dd)] with 1 N sodium hydroxide in methanol yielded tert-butyl (3RS,4RS)-4-(4-carboxymethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, condensation of which with benzylamine in the presence of HBTU analogously to Example 36 (b) gave tert-butyl (3RS,4RS)-4-[4-(benzylcarbamoyl-methoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellowish solid; MS: 598 (M+NH4)+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].[CH2:18]=O.Cl>O>[CH2:18]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1
Reactant: C=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
L-tryptophan (10.2 g, 50 mmol), NaOH (2.0 g, 50 mmol) and H2O (20 ml) were added in a 250 ml round-bottom flask, and were stirred until the mixture became clear followed by the addition of formaldehyde (37%, 50 mmol). The mixture was stirred and reacted at room temperature for 3 h. After being refluxed for another 3 h, the mixture was poured into 200 ml cold water. While being stirred, the mixture was adjusted to pH 6 with 5N HCl. White solids were precipitated and then stored at 4° C. overnight. The white solids were filtered, washed well with water and a small amount of methanol, dried, and recrystallized with methanol to obtain white solids (9.2 g, 85%), mp 308-309° C. (reference: 309-310° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[C:13]([C:18]1[CH:30]=[C:29]([C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])[CH:28]=[CH:27][C:19]=1[O:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])([CH2:16][CH3:17])([CH3:15])[CH3:14].[Cl-].[NH4+].O>C(#N)C.C(O)(C)C>[NH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:1][C:22](=[O:23])[CH:21]([O:20][C:19]2[CH:27]=[CH:28][C:29]([C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[CH:30][C:18]=2[C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])[CH2:25][CH3:26])=[C:3]([OH:12])[CH:4]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Solvent: CC#N
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)cc1O

Procedure:
20 g of 2-amino-4-chloro-5-nitrophenol was dispersed in 150 ml of acetonitrile to which 37.7 g of 2-(2,4-di-tert-amylphenoxy)butanoyl chloride was added dropwise under refluxing. After refluxing for 4 hours, the reaction mixture was cooled to deposit crystals. The crystals were collected by filtration, washed with acetonitrile and dried to yield 49.5 g thereof. 49 g of the crystals were refluxed with stirring for 1 hour together with 28 g of reduced iron powder, 2.7 g of ammonium chloride, 50 ml of water and 500 ml of isopropanol. After removing the iron powder by filtration, the filtrate was cooled to deposite the crystals. The crystals were collected by filtration and dried to obtain 42.4 g of the above described compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([F:16])[CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([F:16])[CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCN(CC)S(=O)(=O)c1ccc(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1F
Reaction time: 16 h
Yield: 31.8 %

Procedure:
According to general procedure B, 4-bromo-N,N-diethyl-2-fluorobenzenesulfonamide (183 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-diethyl-2-fluorobenzenesulfonamide (63 mg, 32%) was provided after purification. MS (ESI) m/z 335. HPLC purity 100.0% at 210-370 nm, 9.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:20].[K+]>O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][OH:10])=[CH:3][C:2]=1[I:20]
Reactant: [I-]
Reactant: Nc1cc(CO)ccc1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: OCc1ccc(F)c(I)c1
Temperature: 60 °C
Yield: 50.8 %

Procedure:
The product from Example 12A (7.0 g, 50 mmol) in water (100 mL) at 0° C. was treated slowly with concentrated sulfuric acid (30 mL) at a rate to maintain the temperature below 10° C. and then treated dropwise with an aqueous solution of sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated at 60° C. for 2 hours, cooled and extracted with methylene chloride. The methylene chloride layer was washed with 10% sodium hydroxide, washed with 1 M sodium thiosulfate, washed with 10% hydrochloric acid, washed with aqueous sodium bicarbonate, dried (sodium sulfate), filtered and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 7:3) to provide 6.4 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].Cl[C:13]1[C:18]([C:19](OCC)=[O:20])=[CH:17][N:16]=[C:15]([S:24][CH3:25])[N:14]=1.C(N(CC)CC)C>C(#N)C>[CH3:25][S:24][C:15]1[N:16]=[C:17]2[N:6]=[C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[NH:7][C:19](=[O:20])[C:18]2=[CH:13][N:14]=1
Reactant: COc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Temperature: 2 °C
Reaction time: 18 h

Procedure:
2-Methoxybenzamidine (from sodium, 0.15 g, in ethanol, 20 ml, and 2-methoxybenzamidine methanesulphonate, 1.70 g) was dissolved in acetonitrile (20 ml) and the resulting cooled (2° C.) solution was added to a cooled (2° C.) suspension of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (2.33 g) in acetonitrile (20 ml). Triethylamine (0.66 g) was added and the reaction mixture was stirred at 2° C. for one hour and at ambient temperature for 18 hours. Acetonitrile was removed under reduced pressure and water (25 ml) was added. The mixture was cooled and a white solid was collected, washed with water and recrystallised from ethanol to yield the title compound, 0.46 g, m.p. 229°-231° C. (dec.).