Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12.C[Si](NC(N[Si](C)(C)C)=O)(C)C.CS([O:52][C:53](=O)[C:54]([C:61]1[N:65]=[C:64]([NH2:66])[S:63][N:62]=1)=[N:55][O:56][CH2:57][C:58]([OH:60])=[O:59])(=O)=O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:66][C:64]1[S:63][N:62]=[C:61]([C:54](=[N:55][O:56][CH2:57][C:58]([OH:60])=[O:59])[C:53]([NH:1][CH:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[CH2:7][S:8][C@H:3]23)=[O:52])[N:65]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Reactant: CS(=O)(=O)OC(=O)C(=NOCC(=O)O)c1nsc(N)n1
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S/C=C\c4cccnc4)CS[C@H]23)ns1
Temperature: 0 °C
Reaction time: 48 h
Yield: 59.8 %

Procedure:
To a solution of benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (3 g) and bis(trimethylsilyl)urea (3.70 g) in tetrahydrofuran (45 ml) was added 2-(5-amino-1,2,4-thiadiazol-3yl)-2-carboxymethoxyiminoacetic methanesulfonic anhydride (syn isomer) (1.45 g) at -30° C. The mixture was stirred at -20~-10° C. for 1 hour, at 0° C. overnight and at ambient temperature for 2 days. The mixture was poured into a mixture of ethyl acetate and a saturated aqueous solution of sodium chloride. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give a precipitate. The precipitate was collected and washed with ethyl acetate and diisopropyl ether in turn to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3yl)-2-carboxymethoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (1.95 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=1[CH3:25])[C:12]([OH:14])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1)#[N:27].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C@@H:11]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=1[CH3:25])[C:12]([NH:35][NH:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[CH:37][CH:36]=1)=[O:14])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
(R)-4-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoic acid (840 mg, 2.19 mmol) and 4-cyanobenzohydrazide (329 mg, 2.41 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (296 mg, 2.19 mmol), TEA (0.458 mL, 3.29 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (630 mg, 3.29 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with water, 5% citric acid followed by 5% NaHCO3 to provide the crude product as a yellow solid (0.95 g). Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white crystalline solid (605 mg, 53%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 9.78 (br s, 2H), 8.03 (d, J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 5.87 (d, J=9 Hz, 1H), 4.40-4.34 (m, 1H), 4.03-3.82 (m, 2H), 2.31 (s, 3H), 2.29-2.04 (m, 2H), 0.81 (s, 9H), 0.1 (s, 3H) and 0.00 (s, 3H).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (1.0 g) in absolute methanol (50 ml) at ambient temperature was added sodium borohydride (1.0 g) in small portions over a period of 30 minutes with vigorous stirring. The mixture was boiled under reflux for 2 hours, cooled to room temperature and the solvent removed under vacuum. The residue was partitioned between water and dichloromethane, the organic layer dried (MgSO4) and evaporated to yield a brown oil (0.81 g) which on chromatography on silica-gel in dichloromethane/methanol mixtures gave a waxy solid. Recrystallisation from 50% 40.60 petroleum ether--ether gave a white solid (0.25 g) m.p. 91°-97° C., as a 58:42 mixture of diastereoisomers.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19][N:18]3[CH3:25])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:42].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O1CCOCC1>[NH2:42][C:28]1[C:27]([CH3:26])=[C:32]([C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19][N:18]4[CH3:25])=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CN1CCN(C)C(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A 250-mL three-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 14 (2.50 g, 6.16 mmol), 7 (1.79 g, 7.70 mmol), 1,4-dioxane (70 mL) and a solution of sodium carbonate (1.96 g, 18.5 mmol) in water (14 mL). After bubbling nitrogen through the resulting mixture for 30 min, tetrakis(triphenylphosphine)palladium (711 mg, 0.62 mmol) was added and the reaction mixture then heated at reflux for 11 h. After this time the reaction was cooled to room temperature and 2N hydrochloric acid (70 mL) followed by ethyl acetate (70 mL) was added. The mixture was stirred for 0.5 h and then filtered through a pad of Celite 521. The organic layer of the filtrate was separated and extracted with 2N hydrochloric acid (2×30 mL). The acidic extracts were combined and washed with ethyl acetate (4×50 mL). The aqueous solution was then stirred vigorously with ethyl acetate (100 mL) while solid potassium carbonate was added portionwise until a pH of 12 was reached. The aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (70 mL) and dried over magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure and dried in a 49° C. vacuum oven for 24 h to afford 15 in 86% yield (2.32 g) as an amber foam: mp 133-134° C.; 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.80 (d, 1H, J=8.5 Hz), 7.29 (d, 2H, J=8.5 Hz), 7.05 (t, 1H, J=8.0 Hz), 6.79 (d, 1H, J=7.5 Hz), 6.73 (d, 1H, J=7.5 Hz), 6.68 (s, 1H), 3.72 (s, 3H), 3.64 (m, 1H), 3.20 (m, 1H), 3.01 (m, 1H), 2.99 (s, 3H), 2.66 (m, 1H), 2.24 (s, 3H), 2.17 (s, 3H); MS (ESI+) m/z 433.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:33])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][C:12]=1SCC1C=CC(OC)=CC=1.O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:33][C:12]2[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: CCOC(=O)Cc1ccc(NC(=S)Nc2ccccc2C)c(SCc2ccc(OC)cc2)c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc2nc(Nc3ccccc3C)sc2c1
Yield: 83.1 %

Procedure:
In ethanol (50 ml), ethyl 4-(N′-(2-methylphenyl)thioureido)-3-(4-methoxybenzylthio)phenylacetate (1.63 g, 3.40 mmol) and mercuric oxide (yellow) (1.10 g, 16.4 mmol) were stirred for one hour at 70° C. Water (50 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1) eluate fractions, ethyl 2-(2-methylphenylamino)-6-benzothiazolylacetate (922 mg, 83%) was obtained as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:23]([CH3:25])[CH3:24]>CC(C)=O.C(Cl)Cl>[CH3:24][CH:23]([O:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[CH3:25]
Reactant: O=[N+]([O-])c1ccc(-n2cccc2)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)Oc1cc([N+](=O)[O-])ccc1-n1cccc1
Yield: 71.1 %

Procedure:
To a stirred mixture of 3.6 g (0.02 mole) of 5-nitro-2-(1H-pyrrol-1-yl)phenol and 3.7 g (0.27 mole) of potassium carbonate in 40 ml of acetone was added 4.5 g (0.027 mole) of 2-iodopropane. After complete addition the mixture was stirred at reflux for approximately 16 hours. The reaction mixture was cooled, and the solvent evaporated under reduced pressure to leave a residue. The residue was dissolved in methylene chloride, filtered, and the filtrate evaporated under reduced pressure to leave residue. The residue was purified by column chromatography on silica gel, eluting with toluene, to yield 3.5 g of 1-(1-methylethoxy-4-nitrophenyl)pyrrole (mp 59°-61° C.).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][OH:10])OCC[O:3]1>CC(C)=O>[OH:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][C:2](=[O:3])[CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCC(CO)CC1(C)OCCO1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCC(CO)CC(C)=O
Yield: 65.8 %

Procedure:
A mixture of about 21 g of 2-methyl-β-octadecyl-1,3-dioxolan-2-propanol in about 220 ml of acetone, about one ml of concentrated (about 12N) hydrochloric acid and about 15 ml of water was refluxed for about 20 minutes, poured into a solution of saturated sodium chloride and extracted with ether. The ether extract was washed with aqueous sodium bicarbonate, dried and the solvent removed. The residue was chromatographed via HPLC, eluting with hexane:ethyl acetate (about 9:1). The solvent was removed from the product fraction, giving about 12.3 g of the desired title compound as a white solid.
Reaction SMILES: NC[C@@H]1OC(=O)N(C2C=CC(S(C)=O)=C(F)C=2)C1.[N:19]([CH2:22][C@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH2:38][F:39])=[O:36])=[C:31]([F:40])[CH:30]=2)[CH2:24]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:19][CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH2:38][F:39])=[O:36])=[C:31]([F:40])[CH:30]=2)[CH2:24]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(S(=O)CCF)c(F)c2)C(=O)O1
Agent: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NC[C@H]1CN(c2ccc(S(=O)CCF)c(F)c2)C(=O)O1

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one from 5-(S)-azidomethyl-3-[4′-(2″-fluoroethyl)sulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.275 g, 0.833 mmol) and triphenylphosphine (0.229 g, 0.874 mmol). Yield 0.253 g (80%). MS (m/z): [M+H]+=305.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[CH2:10]2.C(O)C.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH3:20][CH:19]([NH:22][C@@H:2]1[CH2:3][C:4]2[C:9](=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=2[O:14][CH3:15])[CH2:10][C@H:11]1[OH:1])[CH3:21]
Reactant: CC(C)N
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Solvent: CCO
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](NC(C)C)C2

Procedure:
A mixture of 10.3 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene in 50 ml of isopropylamine containing 2.93 ml of absolute ethanol is heated overnight in a small Parr bomb at 105° C ± 5° C (internal pressure = 75-100 psi). The cooled reaction mixture is concentrated in vacuo to 11.51 g of tan solid. Trituration with ether gives 10.1 g of material, melting point 141-144° C. Two recrystallizations from ethyl acetate give 7.0 g of trans-1,2,3,4-tetrahydro-3-[(1-methylethyl)amino]-5,8-dimethoxy-2-dimethoxy-2-naphthalenol, melting point 144°-145° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[CH:3]=1.[BH4-].[Na+].O.Cl>O1CCCC1.CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[CH:3]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(C=O)cc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(CO)cc2)c1
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
To a solution of the title compound provided by Example 12 (25 mg, 0.068 mmol) in tetrahydofuran (5 ml) and methanol (10 ml) was added sodium borohydride (20 mg, 0.53 mmol). After stirring for 1.5 hours, the mixture was treated with water (10 ml) and hydrochloric acid (1 M, 0.6 ml). The mixture was concentrated to a volume of 8 ml and the solid was collected by filtration. The solid was treated with aqueous sodium carbonate solution (10%, 10 ml) and extracted with ethyl acetate (3×30 ml). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with methanol-dichloromethane (5:95) to give the title compound (10 mg, 39% yield). 1H NMR (acetone-d6) δ1.36 (t, 3H, J=6.9 Hz, CH3), 3.95 (bs, 1H, OH), 4.09 (q, 2H, J=7.0 Hz, CH2), 4.56 (s, 2H, CH2), 5.28 (bs, 2H, NH2), 6.16 (d, 1H, J=1.1 Hz, Ar), 6.34 (d, 1H, J=1.1 Hz, Ar), 7.09 (d, 1H, J=8.5 Hz, Ar), 7.24 (d, 2H, J=8.8 Hz, Ar), 7.30-7.34 (m, 2H, Ar), 7.60-7.63 (m, 2H, Ar), 7.80 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:12][O:11][C:10]([NH2:13])=[N:9]3)=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: NC1=NC(c2ccc(Br)cc2)CO1
Reactant: OB(O)c1ccc(Cl)cc1
Product: NC1=NC(c2ccc(-c3ccc(Cl)cc3)cc2)CO1

Procedure:
In analogy to example 30, (RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine was reacted with 4-chlorophenylboronic acid to give (RS)-4-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine. Off-white solid. MS (ISP): 273.1 ([M+H]+)
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15](C2C=CC=CC=2C([O-])=O)=[CH:14][C:13]=1[N+:27]([O-:29])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C[O:33]CC1.Cl>CO.O>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:33])=[CH:14][C:13]=1[N+:27]([O-:29])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: O=C([O-])c1ccccc1-c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc(O)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 95 %

Procedure:
Lithium hydroxide monohydrate (5.632 g, 134.2 mmol) was added to a stirred solution of compound 53 (2.343 g, 6.71 mmol) in 150 ml methanol and 50 ml water. THF (50 ml) was added after 20 minutes to increase solubility. The reaction mixture was stirred overnight and was then acidified with concentrated HCl. The reaction mixture was extracted five times with dichloromethane, and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified via flash chromatography over silica gel with gradual elutions from 80/10-50/50 (Hex/EtOAc). Evaporation of solvent yielded 1.567 g (95%) of a yellow solid.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[CH:24][C:23]2[CH:26]=[N:27][N:28]([C:29]3[N:34]=[C:33]([N:35]4[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36]4)[CH:32]=[CH:31][CH:30]=3)[C:22]=2[CH:21]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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]>[C:1]([N:5]1[CH:9]=[C:8]([C:20]2[N:25]=[CH:24][C:23]3[CH:26]=[N:27][N:28]([C:29]4[N:34]=[C:33]([N:35]5[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36]5)[CH:32]=[CH:31][CH:30]=4)[C:22]=3[CH:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Reactant: CC(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cnn(C(C)(C)C)c5)cc43)n2)CC1
Temperature: 100 °C
Yield: 52.8 %

Procedure:
A mixture of 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (220 mg, 0.88 mmol), tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (377 mg, 0.88 mmol), and Pd(dppf)Cl2 (64 mg, 0.088 mmol) in 1,4-dioxane (20 mL) and Na2CO3 (2.0 M, 5 mL) under nitrogen was heated at 100° C. for 20 hours. The crude product was purified by silica gel chromatography using petroleum ether:EtOAc (50%-100%) as eluting solvents to afford tert-butyl 4-(6-(6-(1-tert-butyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (240 mg, 53%). MS (ESI) m/z: 517 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH2:10].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH:10][S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: Cn1cccc1C(CCN)c1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cccc1C(CCNS(=O)(=O)c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
3-(1-Methyl-2-pyrrolyl)-3-(3-pyridyl)propylamine (0.59 g) and triethylamine (0.31 g) were dissolved in 20 ml of methylene chloride, followed by addition of 0.64 g of p-chlorobenzene sulfonylchloride, and stirred at room temperature for 18 hours. To the reaction mixture was added 2N hydrogen chloride, and the organic phase was separated, which was then extracted with methylene chloride from the aqueous phase. After washing in saturated aqueous sodium hydrogencarbonate and in aqueous saturated sodium chloride solution and drying over magnesium sulfate, the solvent was distilled off to obtain 0.96 g of N-[3-(1-methyl-2-pyrrolyl)-3-(3-pyridyl)propyl ]-4-chlorobenzenesulfonamide.
Reaction SMILES: [CH3:1]C(C1NC(=O)N(CC=C)C1=O)C.N1C2C(=CC=CC=2)[CH:16]=[C:15]1[CH2:23][CH:24]1[NH:28][C:27](=[O:29])[N:26]([CH2:30][CH:31]=[CH2:32])[C:25]1=[O:33]>>[CH3:1][CH:15]([CH3:16])[CH2:23][CH:24]1[NH:28][C:27](=[O:29])[N:26]([CH2:30][CH:31]=[CH2:32])[C:25]1=[O:33]
Reactant: C=CCN1C(=O)NC(C(C)C)C1=O
Reactant: C=CCN1C(=O)NC(Cc2cc3ccccc3[nH]2)C1=O
Product: C=CCN1C(=O)NC(CC(C)C)C1=O

Procedure:
5-(1-methylethyl)-3-(2-propenyl)-2,4-imidazolidinedione; 5-(1H-indol-2-ylmethyl)-3-(2-propenyl)-2,4-imidazolidinedione;
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH:17]=1)([CH3:4])([CH3:3])[CH3:2].C(OB(OC(C)C)OC(C)C)(C)C.C(NC(C)C)(C)C.[Li].[Cl:40][C:41]1[N:46]=[C:45](Cl)[CH:44]=[CH:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:43]3[CH:44]=[CH:45][N:46]=[C:41]([Cl:40])[N:42]=3)[S:14][C:13]=2[CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCc1ccc2ccsc2c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Temperature: -78 °C
Yield: 28.3 %

Procedure:
Benzo[b]thiophen-6-ylmethyl-carbamic acid tert-butyl ester (3.6 g, 13.8 mmol) is dissolved in THF (100 mL) and cooled to −78° C. Triisopropylborate (8.5 mL) is added, followed by lithium diisopropylamine solution (27 mL of 2.0 M solution), and the reaction is allowed to slowly warm to room temperature over two hours. The reaction is stirred at room temperature for two hours at which time 2,4-dichloropyrimidine (4.59 g, 30.8 mmol), 1,1′-bis(diphenylphosphino)ferrocene (388 mg, 0.700 mmol), palladium (II) acetate (164 mg, 0.730 mmol) and sodium carbonate (28 mL of 2.0 N solution) are added. The reaction is heated for 20 hours at 70° C. After the reaction solution is cooled to 25° C., water (100 mL) is added. The mixture is extracted with dichloromethane and the extracts are evaporated. The resulting solid is subjected to chromatography on silica gel, eluting with EtOAc/hexanes 5-50%, to give the title compound (1.47 g, 28% yield). ES+(m/z) 376 (35Cl) and 378 (37Cl) [M+H].