Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[C:11]1([C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:26][C:27]([NH2:29])=[O:28]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:29][C:27](=[O:28])[NH:26]2)=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2ccc(Br)c(F)c2)N1
Yield: 61.4 %

Procedure:
To a mixture of 4-bromo-3-fluorobenzaldehyde (100 mg, 0.5 mmol), 1,2-diphenylethanone (118 mg, 0.6 mmol) and urea (90 mg, 1.5 mmol) in ethanol (3 mL) was added conc. HCL (0.1 mL). The mixture was refluxed under N2 atmosphere for 6 hrs. Solvent was removed; purified by silica gel column chromatography (PE:EtOAc=10:1 to PE:EtOAc=1:1) to give product (130 mg, yield 62%). 1H NMR (DMSO-d6 400 MHz): δ 8.74 (s, 1H), 7.74-7.68 (m, 1H), 7.54 (s, 1H), 7.26-7.15 (m, 7H), 7.03-6.95 (m, 3H), 6.81-6.79 (m, 2H), 5.24 (d, J=2.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.[NH4+]=[S:36].O>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19](=[S:36])[NH2:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C#N)ccc23)CC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C(N)=S)ccc23)CC1
Temperature: 100 °C

Procedure:
A microwave tube with a 5 ml capacity is charged with 45 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile, prepared in example 12, and 0.2 ml of a 20% aqueous solution of ammonium sulphide in 2 ml of methanol. The mixture is microwave-heated at 100° C. for 20 min (power set at 100 watts) and then poured into 50 ml of water and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The solid obtained is triturated in diisopropyl ether. The insolubles are filtered off under RP and dried under vacuum to give 36 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbothioamide (yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.66 (m, 2 H) 2.11 (m, 2 H) 2.88 (s, 3 H) 2.90 (m, 2 H) 3.56 (m, 2 H) 3.79 (m, 1H) 6.10 (d, J=8.3 Hz, 1 H) 7.33 (t, J=7.8 Hz, 2 H) 7.68 (m, 1 H) 8.18 (broad s, 1 H) 8.34 (dd, J=8.3, 1.5 Hz, 1 H) 8.40 (d, J=8.3 Hz, 1 H) 9.74 (broad s, 1 H) 10.01 (broad s, 1 H) 12.87 (broad m, 1 H) LC-MS-DAD-ELSD: 517 (+)=(M+H)(+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=[CH:33][CH:32]=1>>[C:10]1([CH2:9][CH:5]([CH2:4][CH2:3][CH2:2][O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[C:6]([O:8][CH2:32][CH3:33])=[O:7])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[C:10]1([CH2:9][CH:5]([CH2:4][CH2:3][CH2:2][O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[C:6]([O:8][CH3:32])=[O:7])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C(CCCO)Cc1cccc2ccccc12
Product: CCOC(=O)C(CCCOS(=O)(=O)c1ccc(C)cc1)Cc1cccc2ccccc12
Product: COC(=O)C(CCCOS(=O)(=O)c1ccc(C)cc1)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.31 g of the mixture of the ethyl ester and methyl ester of (2RS)-5-hydroxy-2-(1-naphthylmethyl)pentanoic acid was dissolved in 35 ml of dry pyridine, and 1.69 g of p-toluenesulfonyl chloride was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and 200 ml of ethyl acetate was added to the residue. The ethyl acetate layer was washed with a 5% potassium hydrogensulfate aqueous solution, with a 5% sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to obtain 643 mg of ethyl (2RS)-2-(1-naphthylmethyl)-5-p-toluenesulfonyloxypentanoate, 184 mg of methyl (2RS)-2-(1-naphthylmethyl)-5-p-toluenesulfonyloxypentanoate and 650 mg of a mixture of the two compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.Cl[C:27](Cl)([O:29][C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH2:38](O)[CH2:39][CH2:40][CH2:41][CH2:42]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30](=[O:36])[O:29][CH2:27][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: CCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1[N+](=O)[O-]
Yield: 79.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-hexanol (45 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (109 mg, yield 80%).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.C1C=NC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1.Cl>CN(C=O)C.C(N(CC)CC)C>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(-c2nn[nH]n2)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC(=O)c2ccc(-c3nn[nH]n3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2H-tetrazol-5-yl)benzoic acid (example 412, 4 mmol) and HOAt (4.2 mmol) in DMF (6 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.2 mmol) and the resulting mixture was stirred at room temperature for 1 hour. An aliquot of this HOAt-ester solution (0.45 mL) was mixed with 0.25 mL of a solution of 4-aminobenzoic acid (1.2 mmol in 1 mL DMF). (Anilines as hydrochlorides can also be utilised, a slight excess of triethylamine was added to the hydrochloride suspension in DMF prior to mixing with the HOAt-ester.) The resulting mixture was shaken for 3 days at room temperature. 1N hydrochloric acid (2 mL) was added and the mixture was shaken for 16 hours at room temperature. The solid was isolated by centrifugation (alternatively by filtration or extraction) and was washed with water (3 mL). Drying in vacuo at 40° C. for 2 days afforded the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH:8]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[O:7]1[CH:8]=[C:4]([CH2:3][CH2:1][NH2:2])[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]1=2
Reactant: N#CCc1coc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCc1coc2ccccc12

Procedure:
A solution of 3.97 grams (0.025 mole) of 3-cyanomethylbenzo[b]furan in 200 milliliters of diethyl ether was slowly added to a refluxing suspension of 3.84 grams (0.1 mole) of lithium aluminum hydride in 400 milliliters of ether and the mixture was heated 3 hours, then cooled and water was slowly added. The suspension was filtered and the filtrate was evaporated to obtain an oily product, the hydrochloride salt of which has m.p. 183°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.Cl[C:37](=O)[C:38]([O:40][CH3:41])=[O:39]>O>[CH3:41][O:40][C:38]([C:37]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]2[C:14]([C:12](=[O:13])[C:11]=1[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:28])=[CH:9][CH:8]=1)=[CH:19][CH:18]=[C:17]([Cl:20])[CH:16]=2)=[O:39]
Reactant: COC(=O)C(=O)Cl
Reactant: COC(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Cc2c(C(=O)OC)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A 1 L round-bottomed flask equipped with a magnetic stir bar, a water cooled reflux condenser, a nitrogen bubbler and a thermometer was charged with 4-[3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propyl]-benzoic acid methyl ester (54 g, 137 mmol), toluene (2 L, 18.8 mol) and methyl 2-chloro-2-oxoacetate (200 mL, 2.17 mol). The resulting mixture was heated to reflux overnight. At this time, the reaction mixture was concentrated to a thick gum. This residue was dissolved in methanol (1 L), treated with potassium carbonate (31 g) and stirred overnight. At this time, the reaction was filtered to remove solids. The filtrate was treated with acetic acid (50 mL) and then concentrated in vacuo. The residue was absorbed onto silica gel. Flash chromatography (2″×6″ column; 50-66% ethyl acetate/hexanes) followed by concentration of the appropriate fractions produced a solid. This solid was slurried with 1:1 ethyl acetate/hexanes, collected by filtration and dried in vacuo to afford 7-chloro-3-(4-methoxycarbonyl-benzyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (34 g, 53.7%) as an off-white solid. This material was used without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)CO.[OH-].[K+]>O>[CH:1]1([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(OC2CCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)c1ccc(OC2CCCC2)cc1

Procedure:
To 50 g of methyl p-hydroxybenzoate were added 82 g of cyclopentyl bromide. The mixture was cooled to 0° C. and 24 g of sodium hydride (in a 50% mineral oil suspension) were added in small portions. Ice bath cooling was continued until the resulting effervescence terminated. The reaction mixture then was heated to 75° C. for four hours, cooled, and 25 mL of ethanol was added dropwise. The resulting mixture was evaporated to dryness, and the residue was dissolved in a mixture of water and ether. The ether layer was separated and washed with cold 5% aqueous sodium hydroxide and then with water. The ether layer then was dried over magnesium sulfate and evaporated to dryness to give about 72 g of crude methyl p-cyclopentyloxybenzoate. The crude ester was added to 400 mL of ethylene glycol containing 100 g of potassium hydroxide. The mixture was refluxed for several hours and then was transferred to a 4 L beaker. A mixture of ice and water was added. The resulting mixture then was placed in a separatory funnel and was washed with ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 44.1 g of p-cyclopentyloxybenzoic acid. A solution of 8.7 g (0.024 mole) of p-cyclopentyloxybenzoic acid in 250 mL of anhydrous ether was prepared. The solution was cooled to 5° C.-10° C. and 8.85 g of thionyl chloride followed by two drops of pyridine were added. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture then was evaporated to dryness, and the oily residue of p-cyclopentyloxybenzoyl chloride was dissolved in 150 mL of 1,2-dichloroethane for use as described in Example 10 below.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=O)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=[CH:21][CH:22]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1ccc(CN2CC3CC3(c3ccc(Cl)cc3)C2)cc1

Procedure:
A 16.60 g portion of 3-(p-chlorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane (prepared above) is dissolved in 160 ml of benzene and 55.5 g of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution) is added dropwise. The mixture is refluxed for 2 hours, cooled and quenched slowly with 10 N sodium hydroxide. Water is added, the organic layer is separated and washed 3 times with water and then dried over sodium magnesium sulfate. Removal of the solvent yields an off-white solid, mp 88°-92° C.
Reaction SMILES: [N:1]#[C:2]Br.C([O-])([O-])=O.[K+].[K+].Cl.C[N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)[CH2:14][CH2:13]1.O>CS(C)=O>[C:27]1([N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:2]#[N:1])[CH2:13][CH2:14]3)=[N:19]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a mixture of cyanogen bromide (5.76 g, 0.054 moles) and K2CO3 (8.82 g, 0.064 moles) in dimethylsulfoxide (110 ml) was added 3-(1-methyl-4-piperidinyl)-1-phenyl-1H-indazole (14.8 g, 0.051 moles) of Example 66 in dimethylsulfoxide (DMSO) (15 ml). The reaction was stirred at ambient temperature for 16 hours and then poured into water and extracted with ether. A precipitate formed in the ether which was collected and then the ether was concentrated to yield additional product. The crude product (11.5 g) was recrystallized three times from isopropyl alcohol which yielded 6.75 g (37%) of 4-(1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 124°-125° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1)#[N:2].[C:12]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([CH2:35]Cl)=[O:34])=[CH:28][CH:27]=1)(=[O:19])=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:12]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([CH2:35][C:8]2[NH:9][C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][C:6]=3[N:7]=2)=[O:34])=[CH:30][CH:31]=1)(=[O:18])=[O:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)CCl)cc1
Reactant: N#Cc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2nc3ccc(C#N)cc3[nH]2)cc1
Yield: 16.4 %

Procedure:
Alkylation of 5-cyanobenzimidazole (2 mmol) with (4-(2-tert-butylaminosulfonylphenyl)phenyl-aminocarbonyl]methylene chloride (2 mmol) in DMF (10 mL) and K2CO3 (4 mmol) at r.t. over 16 hours, followed by purification on thin layer TLC plates, and further isolation by HPLC gave [4-(2-tert-butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-6-cyanobenzimidazole (240 mg, 56%) and [4-(2-tert-butylaminosulfonylphenyl)phenylaminocarbonyl]methyl-5-cyanobenzimidazole (160 mg, 37%).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)[S:4][N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])O1.C([O-])([O-])=O.[K+].[K+].CC#N>O>[OH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)[S:4][N:3]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: CC(C)COC(=O)NC1CCN(c2nc(Br)ns2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)COC(=O)NC1CCN(c2nc(-c3ccccc3O)ns2)CC1
Temperature: 175 °C

Procedure:
A mixture of isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate (0.38 g, 1.1 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (0.35 g, 1.6 mmol), Pd(Ph3)4 (12 mg, 11 μmol), K2CO3 (0.29 g, 2.1 mmol), CH3CN (3.0 mL), and H2O (0.3 mL) was sealed in a microwave vessel and heated by microwave irradiation at 175° C. for 15 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to yield isobutyl 1-(3-(2-hydroxyphenyl)-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z 377.3 (M+H)+ at 3.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][Cl:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][Cl:18])[CH2:10][CH2:9]1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCCl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4.94 g tert-Butyl-1-piperazine-carboxylate and 12.66 g 1-Bromo-3-chloropropane in 15 ml DMF (dry) was added 4.08 g K2CO3 and the reaction heated to 50° C. for one minute and stirred at room temperature for additional 3 h. The reaction mixture is pored into 200 ml of water and extracted with DCM. The combined organic phases were washed with water and dried over MgSO4 and evaporated in vacuo. The product was purified by flash column chromatography (n-heptane/ethylacetate 1:1, RF=0.3) Yield 3.9 g.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:17][C:18]1[N:19]=[C:20]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]2)[O:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:1]([O:5][CH2:17][C:18]1[N:19]=[C:20]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]2)[O:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)N1CCC(c2nc(CCl)c(-c3ccccc3)o2)CC1
Reactant: CC(C)CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nc(COCC(C)C)c(-c3ccccc3)o2)CC1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of isobutyl alcohol (0.54 mL, 5.8 mmol) in THF (5 mL) is cooled to 0° C. and treated with sodium bis(trimethylsilyl)amide (5.8 mL of a 1 M solution in THF, 5.8 mmol) and stirred for 1 h. A solution of 1-[4-(4-chloromethyl-5-phenyl-oxazol-2-yl)-piperidin-1-yl]-ethanone (1.69 g, 5.3 mmol), prepared as in Part B, in THF (30 mL) is added dropwise, and the mixture is allowed to warm to 23° C., and stirred for 18 h. The reaction mixture is partitioned between EtOAc (150 mL) and H2O (75 mL), and the organic layer is washed with brine (1×100 mL), dried (MgSO4), and concentrated. The residue is purified by chromatography on silica using EtOAc as eluent to afford the title compound as a yellow oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]2[C:11]([N:13]3[CH:17]([OH:18])[CH2:16][CH2:15][CH:14]3[CH:19]=[N:20][C:8]2=[CH:7][C:6]=1[OH:21])=[O:12]>>[CH3:3][O:4][C:5]1[CH:10]=[C:9]2[C:11](=[O:12])[N:13]3[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[OH:18])[CH:19]=[N:20][C:8]2=[CH:7][C:6]=1[OH:21].[CH3:3][O:4][C:5]1[CH:10]=[C:9]2[C:11]([N:13]3[C@H:17]([OH:18])[CH2:16][CH2:15][C@H:14]3[CH:19]=[N:20][C:8]2=[CH:7][C:6]=1[OH:21])=[O:12]
Reactant: COc1cc2c(cc1O)N=CC1CCC(O)N1C2=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1O)N=C[C@@H]1CC[C@@H](O)N1C2=O
Product: COc1cc2c(cc1O)N=C[C@@H]1CC[C@H](O)N1C2=O

Procedure:
Crystalline methylneothramycin A (225 mg.) obtained in Example 8 was dissolved in 45 ml. of 0.01 NCHl-dioxane (1:1 in volume) and the solution was kept at room temperature (22° C.) for 1 hour. The solution was adjusted to pH 6.0 with 1 N NaOH and concentrated to dryness under reduced pressure, affording 216 mg. of a colorless powder containing neothramycins A and B. The powder was chromatographed on a column of silica gel (20 g.) by the similar manner as employed in Example 2. Pure neothramycin A (87 mg.) and neothramycin B (69 mg) were obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=[O:2].[C:6]1([N:12]2C=[CH:15][CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:17](Cl)[CH2:18]Cl>>[C:6]1([N:12]2[CH:13]=[CH:14][CH:15]=[C:17]2[CH:18]=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCCCl
Reactant: c1ccc(-n2cccc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Phosphorus oxychloride (0.7 mL, 7.68 mmol) was added slowly to ice-cold dimethylformamide (0.6 mL, 7.68 mmol). The mixture was warmed to room temperature and stirred for 15 min. A solution of 1-phenylpyrrole (1.0 g, 6.98 mmol) in ethylene dichloride (5 mL) was added and the reaction mixture heated at reflux for 1 h. The mixture was cooled to 10° C. and quenched into 10% sodium acetate solution (20 mL). The organic layer was separated and the aqueous phase was extracted with ether. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under in vacuo to give a crude residue. Purification by column chromatography over silica gel (60-120 mesh) using 2% ethyl acetate in petroleum ether as eluent gave 1-phenylpyrrole-2-carbaldehyde (700 mg, 59%) as a colourless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2[N+](=O)[O-])CC1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+](=O)[O-])CC1

Procedure:
A solution of 64.0 g (0.19 mole) of 4-[6-(cyclopropylamino)-3-nitro-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 115 ml of acetic anhydride and 115 ml of acetic acid was heated on a steam bath for 36 hours. The solvents were removed in vacuo, the residue was triturated with a mixture of ethanol and toluene which was also evaporated in vacuo to give 68.3 g of the title compound, mp 90-93° C.