Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C@@H:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[Br:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](=[O:35])[CH2:33]Br)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C@@H:12]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:33][C:32]([C:31]1[CH:36]=[CH:37][C:28]([Br:27])=[CH:29][CH:30]=1)=[O:35])=[O:19]
Reactant: CC1=C(C)C(=O)C([C@H](CCCCCC(=O)O)c2ccccc2)=C(C)C1=O
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=C(C)C(=O)C([C@H](CCCCCC(=O)OCC(=O)c2ccc(Br)cc2)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.8 %

Procedure:
A mixture of (7R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (0.71 g, 2.0 mmoles), p-bromophenacylbromide (0.56 g, 2.0 mmoles), and potassium carbonate (0.30 g, 2.2 mmole) in acetone (15 ml) was stirred for 2.5 hours at room temperature. After the reaction was completed, the solvent was evaporated in a reduced pressure, the residue was taken up in the isopropylether. Working up in the usual manner gave the crude product, which was chromatographed on silica gel column with isopropylether to give p-bromophenacyl (7R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoate (1.09 g, 99%) as an oil.
Reaction SMILES: [Na].[C:2]([NH:4][C:5]([NH:10][CH3:11])=[N:6][CH2:7][CH2:8][SH:9])#[N:3].Cl.[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19]Cl>C(O)C>[C:2]([NH:4][C:5]([NH:10][CH3:11])=[N:6][CH2:7][CH2:8][S:9][CH2:19][C:15]1[N:16]=[CH:17][NH:18][C:14]=1[CH3:13])#[N:3]
Reactant: CNC(=NCCS)NC#N
Reactant: Cc1[nH]cnc1CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (1.43 g) was added, with stirring under nitrogen, to dry ethanol (100 ml). After the sodium had dissolved a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (4.90 g) in dry ethanol (50 ml) was added and the mixture was stirred at room temperature for one hour. 5-Methyl-4-chloromethylimidazole hydrochloride (5.18 g) was added in batches over a period of 1 hour at room temperature. The mixture was then stirred at room temperature, for a further hour and heated at reflux temperature for 1/2 hour. After cooling the mixture was filtered and the filtrate was evaporated to a glassy solid (8.8 g). This crude product was chromatographed on silica gel with acetonitrile as eluant and the solid product obtained (3.60 g) was recrystallised from acetonitrile to give N-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p. = 140°-142° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][OH:3].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[OH:3][CH2:2][CH2:1][NH:4][S:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(NCCO)c1ccccc1
Temperature: 60 °C
Yield: 95.4 %

Procedure:
128.3 g of 2-ethanolamine (2.1 mol) and 150 g of water are introduced into a 1 litre reactor equipped with a thermostatically-controlled jacket, a stirrer and a dropping funnel. 353 g of benzenesulphonyl chloride (2 mol) are introduced into the dropping funnel. The reactor is heated to approximately 60° C. and the benzenesulphonyl chloride is then allowed to run dropwise into the reactor at the rate of approximately 3 ml/min. The exothermicity of the reaction is thus controlled and the temperature changes to reach 70 to 75° C. at the end of addition. The pH is prevented from falling below 9 by gradual addition of a 20% solution of sodium hydroxide in water. After a few hours, the reaction is complete. The reaction mixture is then extracted with a third water-insoluble solvent, such as ethyl acetate. This organic phase is collected. The aqueous phase is extracted and the combined organic phases are distilled under vacuum in order to remove the extraction solvent. 384 g of N-(2-hydroxyethyl)benzenesulphonamide are thus obtained, i.e. a yield of 95.5% with a purity of greater than 99%. This product, which is liquid at room temperature, is characterized by IR spectroscopy and NMR spectro-scopy, as well as by GC and HPLC analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].CC(=CC)C.[O-:23]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH3:2][CH2:1][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([OH:23])=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of 0.104 g (0.413 mmol) of 6-Chloro-3-formyl-1H-indole-2-carboxylic acid ethyl ester in a mixture of tert-butanol (10 ml) and H2O (5 ml), was added 2-methyl-2-butene (2 ml) followed by a solution of NaClO2 (0.344 g, 3.80 mmol) and NaH2PO4 (0.399 g, 2.90 mmol) in water (2 ml). The mixture was stirred overnight at RT. The organic solvents were removed, and then the aqueous solution diluted with water, and washed twice with hexane. The ph of the aqueous phase was adjusted to 3 by addition of aq. HCl 1N, and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 15 mg (14%) of 6-chloro-1H-indole-2,3-dicarboxylic acid 2-ethyl ester as alight yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([O:21][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(OCCCCCCO)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) was treated with 6-chloro-1-hexanol and potassium carbonate in N,N-dimethylformamide at 120° C. to yield the 6-{6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-pyrimidin-4-yloxy}-hexan-1-ol as a yellow amorphous solid; MS: [M+H]+=434.
Reaction SMILES: [NH2:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([NH:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:21])[CH3:20]
Reactant: CC(N)CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A solution of tert-butyl 4-(3-aminobutyl)piperidine-1-carboxylate (3.58 g) and acetic anhydride (4.13 g) in ethyl acetate (100 mL) was heated under reflux for 3 hr. The reaction mixture was allowed to cool to room temperature, washed with aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6](=O)[CH2:5]2.C([BH3-])#N.[Na+].Cl.[CH3:17][NH:18][CH3:19].Cl>CO>[CH3:17][N:18]([CH3:19])[CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1
Reactant: CNC
Reactant: O=C1Cc2ccc(Cl)cc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C1Cc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.4 g. of 5-chloro-2-indanone (0.0025 mole) was partially dissolved in methanol (10 ml.) and 0.4 g. of sodium cyanoborohydride (0.0065 mole) and 0.6 g. of dimethylamine hydrochloride (0.0075 mole) were added. The pH of the mixture was adjusted to 4.5 with 10% hydrochloric acid and 3 A molecular sieves were added. The mixture was stirred for 16 hours at 25° C., acidified, evaporated to dryness, dissolved in 10% hydrochloric acid, extracted with ether, basified and extracted with ether to yield N,N-dimethyl-5-chloro-2-aminoindane.
Reaction SMILES: C([S:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.Cl.C[O:49][C:50](=[O:71])[C:51]1[CH:56]=[CH:55][C:54]([CH2:57][N:58]2[C:62]([CH2:63][NH2:64])=[CH:61][N:60]=[C:59]2[CH2:65][CH2:66][CH2:67][CH3:68])=[C:53]([F:69])[C:52]=1[F:70]>CN(C=O)C>[CH2:65]([C:59]1[N:58]([CH2:57][C:54]2[CH:55]=[CH:56][C:51]([C:50]([OH:71])=[O:49])=[C:52]([F:70])[C:53]=2[F:69])[C:62]([CH2:63][NH:64][C:6](=[O:8])[C@@H:5]([SH:4])[CH2:9][CH:10]([CH3:11])[CH3:12])=[CH:61][N:60]=1)[CH2:66][CH2:67][CH3:68]
Reactant: CCCCc1ncc(CN)n1Cc1ccc(C(=O)OC)c(F)c1F
Reactant: CC(=O)S[C@@H](CC(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1ncc(CNC(=O)[C@@H](S)CC(C)C)n1Cc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
(S)-2-Acetylsulfanyl-4-methylpentanoic acid (205 mg, 1.1 mmol) was dissolved in DMF (8.1 mL, 104 mmol). HATU (409 mg, 1.1 mmol) and DIPEA (170 μL, 1.0 mmol) were added and the mixture was stirred at room temperature for 30 minutes. 4-(5-Aminomethyl-2-butyl-imidazol-1-ylmethyl)-2,3-difluorobenzoic acid methyl ester dihydrochloride salt (401 mg, 1.0 mmol) was dissolved in DMF (1 ml) with DIPEA (170 μL, 1.0 mmol) and added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched with water, and the mixture extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude residue was then redissolved in 1:1 MeOH:NaOH (4 mL) and stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with acetic acid and the mixture was concentrated. The product was purified by preparative HPLC (2-90%) to yield 108 mg of the title compound as a white solid. MS m/z: [M+H+] calcd for C22H29F2N3O3S, 454.19. found 454.2. 1H-NMR (DMSO): 8.44 (1H, t), 7.59 (1H, t), 7.25 (1H, s), 6.62 (1H, t), 5.56 (2H, s), 4.24 (2H, m), 3.14 (2H, q), 2.79 (2H, t), 2.72 (1H, d), 1.2-1.6 (7H, m), 0.78 (6H, d), 0.71 (3H, d).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:18]([Ge:20](Cl)([Cl:23])[CH2:21][CH3:22])[CH3:19]>O1CCCC1.CCCCCC>[Cl:23][Ge:20]([CH2:21][CH3:22])([CH2:18][CH3:19])[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: CC[Ge](Cl)(Cl)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[Ge](Cl)(CC)C1(c2ccccc2)SCCCS1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
19.63 g (0.10 mol) 2-phenyl-1,3-dithian was dissolved under argon in 200 ml anhydrous tetrahydrofuran (THF) in a dry 500-ml three-necked flask with 50 ml dropping funnel, internal thermometer, magnetic stirrer and septum. The solution was cooled to −10° C. 44 ml of a 2.5 molar solution of n-butyllithium (0.11 mol) in n-hexane was added dropwise at −5° C. over a period of 50 min. After the addition was complete, the green solution was stirred for 2 h at 0° C. It was then added dropwise within 45 min to a solution, cooled to −72° C., of 20.16 g (0.10 mol) diethylgermanium dichloride in 500 ml anhydrous THF, wherein the temperature did not exceed −65° C. The reaction mixture was stirred for a further 16 h in a thawing cold bath, then concentrated on the rotary evaporator. 100 ml dry n-hexane was added to the residue followed by stirring for 1 h at room temperature. The suspension was filtered and the filtrate was concentrated on the rotary evaporator and dried under fine vacuum. The oily, yellow crude product was purified by means of high-vacuum distillation (b.p.: 135-150° C./4×10−5 mbar). 27.23 g (75% of the theoretical value) chlorodiethyl(2-phenyl-1,3-dithian-2-yl)germanium was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[O:7]=[C:8]1[CH2:13][N:12]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10][N:9]1[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[O:7]=[C:8]1[CH2:13][N:12]([C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:11][CH2:10][N:9]1[C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 48.3 %

Procedure:
Synthesized according to general procedure 12, method A. The reaction was set up with 2-aminothiazole (2.4 g, 24.2 mmol), anhydrous pyridine (10 mL), and 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride (9.0 g, 24.2 mmol). The dark oil was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by a second purification on silica gel using 80% EtOAc in hexanes to obtain the desired sulfonamide as a white solid (5.1 g, 11.7 mmol, 48% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=435.2; tR=2.35 min.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1>>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [2-(3,5-bis-trifluoromethyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 60) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as yellow solid. MS: 553.1 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]([OH:11])=O)[CH:2]=1.[Cl:12][C:13]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20].ClCCl.CO.N>>[Cl:12][C:13]1[CH:26]=[C:25]([NH:27][C:9](=[O:11])[C:8]#[C:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)C#Cc1cccnc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2cccnc2)cc1Cl

Procedure:
Prepared analogously to Example 2.3.f. from pyridin-3-ylpropynoic acid and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.42 g (66.4% of theory); melting point: 118° C.-120° C.; C20H22ClN3O2 (M=371.86); calc.: molecular ion peak (M+H)+: 372/374; found: molecular ion peak (M+H)+: 372/374; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:56][CH:57]=1
Reactant: COc1ccc(-c2cccc(N)c2)cc1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
DIEA (0.0144 mL, 0.083 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.017 g, 0.075 mmol) and HATU (0.032 g, 0.083 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-biphenyl-3-ylamine (0.015 g, 0.075 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 68% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:34]4[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=4)[CH:28]=[O:29])[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cccc(C=O)c4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with 3-formylphenylboronic acid in General Procedure A to yield 3-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-2-yl]-benzaldehyde. Treatment of this aldehyde with sodium borohydride (2.5 equivalents) in ethanol yielded the desired compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[O:26])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[O:26])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: CC(C)N(C)C(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)N(C)C(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reaction time: 18 h

Procedure:
A mixture of 3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-N-isopropyl-N-methylpropionamide (0.06 g) and 10% Pd/C (0.03 g) in EtOAc (25 mL) is hydrogenated at 1 atm for 18 h. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residual gum is purified by preparative HPLC to afford the title compound as a grey solid: 1H NMR (DMSO-d6□7.21 (d, J=8.08 Hz, 1H), 6.73 (s, 1H), 6.66 (d, J=8.08 Hz, 1H), 4.71-4.64 (m, 0.65H), 4.23 (s, 2H), 4.10-4.02 (m, 0.35H), 2.72 (s, 2H), 2.73-2.54 (m, 4H), 2.64 (s, 1H), 1.07 (d, J=6.57 Hz, 2.5H), 0.99 (d, J=6.57 Hz, 3.5H); (M−1)−=354.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[B:17](OC)([O:20]C)[O:18]C.Cl>O1CCCC1.O.II>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:17]([OH:20])[OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
62 g (0.236 mol) of 3-benzyloxybromobenzene, 6.64 g (0.277 mol) of magnesium and 0.3 g of iodine are reacted in 800 ml of tetrahydrofuran at 60° C. for 2 hours to give the solution of the corresponding Grignard compound, which is subsequently added dropwise to a solution, cooled to 0° C. of 28.77 g (0.277 mol) of trimethyl borate in 300 ml of tetrahydrofuran. The mixture is stirred at 0° C. for 1 hour, 74 ml of 37% strength hydrochloric acid in 300 ml of water are added, and the reaction mixture is subsequently partitioned between water and ether. The organic phase is washed twice with water, dried over sodium sulfate, evaporated and recrystallized from hexane, giving 33.65 g of 3-benzyloxybenzeneboronic acid. ##STR13##
Reaction SMILES: C(O)C.[NH2:4][CH:5]1[C:26](=[O:27])[N:7]2[C:8]([C:13]([O:15]CC3C=CC([N+]([O-])=O)=CC=3)=[O:14])=[C:9]([Cl:12])[CH2:10][S:11][C@H:6]12.Cl>[Fe].O>[NH2:4][CH:5]1[C:26](=[O:27])[N:7]2[C:8]([C:13]([OH:15])=[O:14])=[C:9]([Cl:12])[CH2:10][S:11][C@H:6]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of ethanol (240 ml) and water (50 ml), p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (20 gm) was added. Iron powder (20 gm) was charged at 30° C., followed by the addition of concentrated HCl (25 ml) in an ethanol (930 ml) and water (5.0 ml) mixture over a period of 15 minutes. The reaction mixture was stirred for 1 hour. After completion of the reaction, aq. KHCO3 was added to bring the pH to 8.0, followed by the addition of activated carbon. After stirring for 10 minutes, the mixture was filtered. To the filtrate was added aq. HCl to bring the pH to 4.0. The product thus separated was filtered and dried to yield 8.42 gm (73%) of white crystalline product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:9]1[C:28](O)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH2:37])C>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:18]=[CH:19][CH:20]=[CH:21]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:9]1[C:28]([NH:37][C@H:36]([C:35]([OH:34])=[O:42])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from 1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid and L-leucine ethyl ester hydrochloride followed the procedure of Example 2 Step 4 as a white solid: 1H NMR (DMSO-d6) δ 0.76 (d, J=6.5 Hz, 3 H), 0.77 (d, J=6.5 Hz, 3 H), 1.20-1.40 (m, 1 H), 1.40-1.50 (m, 1 H), 1.50-1.60 (m, 1H), 4.28-4.40 (m, 1 H), 5.55 (d, J=16.1 Hz, 1 H), 5.61 (d, J=16.2 Hz, 1 H), 6.21 (t, J=2.0 Hz, 2 H), 7.20-7.50 (m, 12 H), 7.55-7.65 (m, 3 H), 8.89 (d, J=7.8 Hz, 1 H), 12.64 (br s, 1 H); MS (ESI) m/z 506 (MH+); MS (ESI) m/z 504 ([M-H]−); HRMS calcd for C32H32N3O3: 506.2444; found (ESI+): 506.2429; Anal. calcd for C32H31N3O3.0.25 H2O: C, 75.35; H, 6.22; N, 8.23. Found: C, 75.42; H, 5.86; N, 7.98.