Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([NH:22][C:23]([CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[C:38]([O:45][C@@H:46]3[O:72][C@H:71]([CH2:73][O:74][C:75](=[O:80])[C:76]([CH3:79])([CH3:78])[CH3:77])[C@@H:63]([O:64][C:65](=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67])[C@H:55]([O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C@H:47]3[O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])=[N:39][NH:40]4)=[CH:30][CH:29]=2)=[O:24])([CH3:21])[CH3:20])=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[N:14]1([C:17]([C:19]([NH:22][C:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[C:38]([O:45][C@@H:46]3[O:72][C@H:71]([CH2:73][O:74][C:75](=[O:80])[C:76]([CH3:79])([CH3:78])[CH3:77])[C@@H:63]([O:64][C:65](=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67])[C@H:55]([O:56][C:57](=[O:62])[C:58]([CH3:59])([CH3:60])[CH3:61])[C@H:47]3[O:48][C:49](=[O:54])[C:50]([CH3:51])([CH3:52])[CH3:53])=[N:39][NH:40]4)=[CH:32][CH:33]=2)=[O:24])([CH3:21])[CH3:20])=[O:18])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(C#Cc4ccc(/C=C/CC(=O)NC(C)(C)C(=O)N5CCN(C(=O)OCc6ccccc6)CC5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(CCc4ccc(CCCC(=O)NC(C)(C)C(=O)N5CCNCC5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 4-[2-(4-{(E)-3-[l-{[4-(benzyloxy-carbonyl)piperazin-1-yl]carbonyl}-1-(methyl)ethyl-carbamoyl]prop-1-enyl}phenyl)ethynyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (34 mg) in methanol (3 mL) was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 4-{2-[4-(3-{1-[(piperazin-1-yl)-carbonyl]-1-(methyl)ethylcarbamoyl}propyl)phenyl]ethyl}-3-(2,3,4, 6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (30 mg). This material was dissolved in methanol (3 mL). To the solution was added lithium hydroxide monohydrate (6 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added acetic acid (0.1 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (17 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]([CH3:26])[CH3:25])=[C:17]([NH:27][CH:28]3[CH2:33][CH2:32][N:31](CC4C=CC=CC=4)[CH2:30][CH2:29]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO.C([O-])=O.[NH4+]>[Pd].O>[C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]([CH3:26])[CH3:25])=[C:17]([NH:27][CH:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)n1cnc2c(NC3CCN(Cc4ccccc4)CC3)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)n1cnc2c(NC3CCNCC3)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc21

Procedure:
Add to a solution of trans-{4-[6-(1-benzyl-piperidin-4-ylamino)-9-isopropyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8b, Ig, 1 mmol) and methanol (40 ml), a suspension of palladium black (0.25 g) in a little water. Then add a solution of ammonium formate (0.4 mg, 6.4 mmol) and 10 ml of water, and reflux overnight. Filter the reaction through Celite® and concentrate the filtrate to dryness. Dissolve the residue in methylene chloride (50 ml), extracted with water, and filter through Celite® to remove a milky white precipitate. Separate the organic layer, wash with brine, dry over sodium sulfate, filter and concentrate the filtrate to dryness. Purify the residue on a 40 gram silica gel column (Biotage) using DCM/methanol (4:1) to give 0.8 grams of trans-{4-[9-isopropyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9b). H1-NMR (CDCl3): δ 7.5 (s, 1H), 5.45 (brs, 1H), 4.64 (m, 2H), 4.45 (m, 1H), 4.2 (m, 1H), 3.75 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 3.0 (m, 1H), 2.8 (t, 1H), 2.5-2.0 (m, 9H), 1.6 (m, 2H), 1.53 (d, 6H), 1.45 (s, 9H), 1.25 (m, 3H).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:8]1([Mg]Cl)[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH:8]1([CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[OH:1])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: ON1CCOCC1
Reactant: Cl[Mg]C1CCCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCOCC1C1CCCC1
Reaction time: 1 h
Yield: 29 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclopentylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 70% diethyl ether in hexanes to give the title compound (0.246 g, 29%) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=2[C:21]2[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]3[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=3[C:21]3[CH:41]=[CH:42][CH2:43][CH2:44][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2C2=C1CCC=C2

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared. The reaction was monitored by tlc (Rf=0.35, 3% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6]2.Br[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.CC(C)([O-])C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:60]([OH:67])(=[O:66])/[CH:61]=[CH:62]/[C:63]([OH:65])=[O:64]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C.C(O)C.O.O1CCOCC1>[C:60]([OH:67])(=[O:66])/[CH:61]=[CH:62]/[C:63]([OH:65])=[O:64].[Cl:18][C:15]1[CH:16]=[C:17]([N:5]2[CH2:4][CH:3]3[N:2]([CH3:1])[CH:7]([CH2:8][CH2:9][CH2:10]3)[CH2:6]2)[CH:12]=[CH:13][C:14]=1[Cl:19]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CN1C2CCCC1CNC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1C2CCCC1CN(c1ccc(Cl)c(Cl)c1)C2
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
A mixture of 9-methyl-3,9-diaza-bicyclo[3.3.1]nonane (0.50 g, 3.56 mmol), 1-bromo-3,4-dichlorobenzene (1.61 g, 7.13 mmol), potassium tert-butoxide (0.80 g, 7.13 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.050 g, 0.105 mmol) and palladium (II) acetate (0.025 g, 0.111 mmol) and dioxane (10 ml) was stirred at 110° C. for 20 min. Water (30 ml) was added followed by extraction with ethylactate (3×10 ml). The organic phase was dried and evaporated. The crude product was purified by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (18-1-1%). The pure product was isolated. Yield 211 mg (20%). The fumarate salt was precipitated from 1.1 eq of fumaric acid and a mixture of ethanol and diethylether (2:5). Mp 187-189° C. LC-ESI-HRMS of [M+H]+ shows 285.092 Da. Calc. 285.092529 Da, dev. −1.9 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br

Procedure:
2.8 g of 2-bromo-5-nitroaniline are dissolved in 18 mL of acetic anhydride in a microwave oven reactor. After hermetically closing the reactor and reacting for one hour at 60° C. under microwave irradiation, the solid is filtered off and then washed with three times 10 mL of diethyl ether and dried to give 3 g of N-(2-bromo-5-nitrophenyl)acetamide in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][C:26]([N+:30]([O-])=O)=[CH:27][CH:28]=5)[C:23]([CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])=[CH:22]4)=[O:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([C:19]([C:16]1[CH:17]=[CH:18][C:12]3[O:11][C:10]([C:7]4[S:8][CH:9]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[N:6]=4)=[CH:14][C:13]=3[CH:15]=1)=[O:20])[CH:22]=[C:23]2[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)n4cc(CC(=O)OCc5ccccc5)c5cc([N+](=O)[O-])ccc54)ccc3o2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)n4cc(CC(=O)OCc5ccccc5)c5cc(N)ccc54)ccc3o2)n1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A mixture of benzyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]carbonyl}-5-nitroindol-3-acetate (450 mg), iron powders (450 mg) and ammonium chloride (45 mg) in a mixed solvent of ethanol (7 ml) and water (3 ml) was stirred under reflux for 1 hour. After being cooled to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give benzyl 5-amino-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]carbonyl}indole-3-acetate (259 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>O1CCCC1>[CH2:16]([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)[CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCBr
Reactant: Clc1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCCc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
A solution containing 294 g (2 mol) of 1,4-dichlorobenzene in 500 ml of anhydrous tetrahydrofuran was added dropwise under nitrogen at 80° C. to a stirred suspension of 48.6 g (2.0 mol) of magnesium turnings over the course of 110 min. The mixture was then heated at 80°-84° C. for 2 hours, and the solution of the Grignard compound was decanted off the excess magnesium and added dropwise at 80° C. over the course of 30 min to a stirred solution containing 194 g (1.8 mol) of 6-bromo-1-hexene (available from Fluka GmbH, D-7910 Neu-Ulm) in 200 ml of tetrahydrofuran. The mixture was then stirred at 80° C. for 4 hours and poured onto ice. Acidification with hydrochloric acid was followed by extraction three times with a 1:1 diethyl ether/methyl tert-butyl ether mixture, and the ether fractions were stirred with active carbon and dried over sodium sulfate. The residue after concentration of the filtrate was fractionated under reduced pressure. About 156 g (corresponding to a yield of 40% of theory) of 4-(5-hexenyl)-1-chlorobenzene were obtained at a temperature of 116°-118° C. under a pressure of 13 hPa.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:23])[CH3:22])[O:19][CH:20]=2)[N:11]=1>C(C#N)(C)=O.O=[Mn]=O>[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([C:21](=[O:23])[CH3:22])[O:19][CH:20]=2)[N:11]=1
Reactant: CC(O)c1nc(Cn2ncc(NC(=O)OCc3ccccc3Cl)n2)co1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1nc(Cn2ncc(NC(=O)OCc3ccccc3Cl)n2)co1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of {2-[2-(1-hydroxy-ethyl)-oxazol-4-ylmethyl]-2H-[1,2,3]triazol-4-yl}-carbamic acid 2-chloro-benzyl ester (10 mg, 0.03 mmol) in AcCN (5.0 mL) was treated at rt with MnO2 (13 mg, 0.13 mmol) and the reaction mixture was stirred at 50° C. for 2 h before being filtered through Celite. TLC: rf (EA)=0.60. LC-MS-conditions 02: tR=0.97 min; [M+H]+=376.04.
Reaction SMILES: O.[C:2]1([CH3:12])[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:12][Br:13]
Reactant: COC(=O)c1ccccc1C
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccccc1CBr

Procedure:
A water jacketted, immersion photolysis vessel equipped with a N2 inlet, dropping funnel and a reflux condenser was charged with 1 L of carbon tetrachloride and 127 g. (0.847 mol) of 2-methyl toluate (Pfaltz and Bauer M29200). A solution of 400 ml carbon tetrachloride and 43.5 ml (0.849 mol) of bromine was added to the dropping funnel. After the solution had been heated to reflux the bromine solution was slowly added while the solution was irradiated with a 600 watt incandescent lamp. After the addition of the bromine solution was complete, the lamp was turned off and the solution cooled. The carbon tetrachloride was removed under reduced pressure. The resultant oil was crystallized from 250 ml of a (1:1) solution of diethyl ether and hexane. The solid was collected and washed with hexane to yield 119 g. (61%) of product.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].C(O)C.CC(C)=O>C(O)(=O)C.C(=O)C1C(=CC=CC=1)O>[ClH:1].[NH2:2][CH:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: NCCCC[C@@H](N)C(=O)O
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: NCCCCC(N)C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
6 g of D-lysine monohydrochloride were dissolved in 180 ml of an aqueous 95% acetic acid solution, and 0.34 ml of salicylaldehyde was added thereto. The mixture was stirred at 100° C. for 3 hours. After the reaction, the mixture was condensed. 30 ml of 50% ethanol-acetone were added to the residue, and the crystalline precipitates were collected by filtration. 5.6 g of DL-lysine monohydrochloride were thereby obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([CH3:12])=[C:10]([C:13]#[N:14])[C:9](=[O:15])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:13]([C:10]1[C:9](=[O:15])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]=1[CH3:12])#[N:14]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c(=O)c(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2nc(C(=O)O)c(C)c(C#N)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
To a solution of 5-cyano-4-methyl-1-(4-methoxy-phenyl)-6-oxo-1,6-dihydro-pyridazine-3-carboxylic acid ethyl ester (15 g, 0.048 mol, prepared as described in example 23) in a mixture of ethanol (250 ml) and water (100 ml) was added sodium hydroxide (2.1 g, 0.053 mol). The reaction mixture was stirred at room temperature for 16 h, the volatiles were evaporated and the residue diluted with water (200 ml). The aqueous phase was washed with ethyl acetate (250 ml) and pH was adjusted to pH=2 by addition of concentrated hydrochloric acid. The precipitate was filtered off and washed with water (2×80 ml) and dried in vacuo at 50° C. for 16 h which afforded 12.3 g (90%) of 5-cyano-1-(4-methoxy-phenyl)-4-methyl-6-oxo-1,6-dihydro-pyridazine-3-carboxylic acid as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]2[CH2:17][O:18][CH2:19][CH2:20][C:14]=2[N:13]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]2[CH2:17][O:18][CH2:19][CH2:20][C:14]=2[N:13]=1
Reactant: COC(=O)c1ccc(C)c(-c2nc3c([nH]2)COCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1nc2c([nH]1)COCC2
Temperature: 60 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
A mixture of methyl 4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate (compound 1.10, 210 mg, 0.73 mmol, 1.00 equiv, 95%) and sodium hydroxide (92.65 mg, 2.32 mmol, 3.00 equiv) in 12 mL methanol/H2O (2:1) was stirred for at 60° C. in an oil bath. After 2 h, the reaction mixture was concentrated under reduced pressure and the residue was taken up in 5 mL of H2O. The resulting mixture was washed with 3×10 mL of ethyl acetate and the pH of the aqueous layer was then adjusted to 2-3 using hydrogen chloride (aq., 2 M). The resulting mixture was extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 0.21 g (89%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.C1(N)CCCCC1.C(N)C(C)C.[Na]>C(O)C.C(O)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: [Na]
Solvent: CC(C)CN
Solvent: NC1CCCCC1
Solvent: CC(C)O
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2Cl)cc1
Yield: 55 %

Procedure:
Prepared analogous to example 25 from 4-(2'-chloro-4-biphenylyl)-4-oxo-butyric acid. Yield: 55% of theory. Melting point of the cyclohexylamine salt: 157°-158° C. (from water); melting point of the isobutylamine salt: 131°-133° C. (from isopropanol); the sodium salt has a double melting point of 90°-95° C. and 130°-133° C. (from ethanol).
Reaction SMILES: C[O-].[Na+].[C:4]([NH:7][OH:8])([NH2:6])=[NH:5].[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18](OC)=O)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[O:8][N:7]=[C:4]([NH2:6])[N:5]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: N=C(N)NO
Agent: C[O-]
Agent: [Na+]
Product: Nc1noc(-c2ccc3[nH]ccc3c2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a stirred solution of NaOMe [prepared in-situ from sodium metal (0.261 g, 11.36 mmol) in MeOH (10 mL) at 60° C.] was added hydroxyguanidine (0.863 g, 11.36 mmol) and the resulting mixture was stirred at 60° C. for 30 min. To the above mixture, methyl 1H-indole-5-carboxylate (1 g, 5.68 mmol) was added and the reaction was stirred at 60° C. for 12 h. The reaction was cooled to RT and quenched with H2O (100 mL). The aqueous layer was extracted in EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by triturating with pentane to give 5-(1H-indol-5-yl)-[1,2,4]oxadiazol-3-ylamine (0.1 g, 8.6%) as an off-white solid. MS (ESI, pos. ion) m/z: 201.1 (M+1). 1H-NMR (400 MHz DMSO-d6): δ 11.53 (s, —1H), 8.24 (s, 1H), 7.73 (dd, J=11.6, 2.4 Hz, 1H), 7.56 (m, 2H), 6.61 (s, 1H), 6.29 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[F:22][C:23]([F:27])([F:26])[S:24]Cl>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[C:11]([S:24][C:23]([F:27])([F:26])[F:22])[NH:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: FC(F)(F)SCl
Product: COc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
Following the procedure of Example 1, reaction of 2,3-bis(4-methoxyphenyl)pyrrole with trifluoromethanesulfenyl chloride gave 4,5-bis(4-methoxyphenyl)-2-(trifluoromethylthio)pyrrole as a white solid, m.p. 114°-115°.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.O1CCOCC1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1ccc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc2ncccc2c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
In a 100 ml flask was placed starting material quinolone (4.22 g) and dioxane (40 ml). POCl3 (4.6 g) was added, and the mixture was heated to 75° C. After 2 hours, HPLC showed the reaction finished (99.7% conversion). Reaction mixture was cooled to room temperature, and then poured to 100 ml saturated NaHCO3 solution and 20 ml EtOAc. The resulting suspension was stirred for 3 hours. Product was isolated by filtration, washing with EtOAc and drying under vacuum. Yield: 4.0 g, 90.9%.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].Cl[Si](C)(C)C.[CH3:21][CH2:22]O>>[CH2:10]([C:9]1[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:2]([O:1][CH2:21][CH3:22])=[O:3])=[CH:15][CH:14]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: CCO
Agent: C[Si](C)(C)Cl
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of ibuprofen 1A (9.89 g, 48 mmol) in anhydrous EtOH (35 mL) was added chlorotrimethylsilane (18.27 mL, 144 mmol) at room temperature, and the mixture was stirred at the same temperature for 2h. After the removal of the excess EtOH and chlorotrimethylsilane under reduced pressure, the oily residue was treated with ice-cold saturated NaHCO3 (150 mL), and the resulting mixture was extracted with hexanes (450 mL). The hexanes solution was washed with brine (3×50 mL), and dried over anhydrous Na2SO2. Evaporation of the solvent afforded ethyl 2-(4′-isobutylphenyl)propionate 2A (11.24 g, in 100% yield) as a colorless oil.