Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:15]3=[O:26])[CH:9]=2)[N:4]=1.C([O-])(O)=[O:28].[Na+]>>[CH3:13][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:15]3=[O:26])[CH:9]=2)[NH:4][C:3](=[O:28])[CH:12]=1
Reactant: Cc1ccncc1N1CCN(c2ccc3nc(Cl)cc(C)c3c2)C1=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: Cc1ccncc1N1CCN(c2ccc3[nH]c(=O)cc(C)c3c2)C1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 80.85 %

Procedure:
1N HCl (5 mL) was added to 1-(2-chloro-4-methyl-quinolin-6-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (21A: 50 mg, 0.1418 mmol). The reaction mixture was stirred at 120° C. overnight. The reaction mass was cooled to 0° C., aqueous NaHCO3 was added till a pH of about 8 was attained. The reaction mixture was extracted with chloroform. The organic layer was dried over Na2SO4 and concentrated to afford 38 mg of the product (80.85% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:6]=1.N1C=CC=CC=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:22][S:19]([NH:1][C:2]1[S:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:6]=1)(=[O:21])=[O:20]
Reactant: CCOC(=O)Cc1cnc(N)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cnc(NS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of ethyl 2-aminothiazol-5-ylacetate (32 g.) in methylene chloride (160 ml.) was added pyridine (27.2 g.) under ice-cooling, and to the mixture was dropwise added mesyl chloride (29.6 g.) in methylene chloride (29.6 ml.) over 30 minutes at 8° to 10° C. The mixture was further stirred for 8 hours at room temperature. After the reaction, methylene chloride was distilled off from the reaction mixture, and to the residue were added water (300 ml.) and ethyl acetate (300 ml.). The resulting mixture was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, and the precipitates were collected by filtration and washed with ethyl acetate. The precipitates were recrystallized from ethanol (600 ml.) to give ethyl 2-methanesulfonamidothiazol-5-ylacetate (27.3 g.), mp 153° to 155° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:74][C:73]3[CH:75]=[CH:76][C:70]([F:69])=[CH:71][CH:72]=3)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)Nc3ccc(F)cc3)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 4-fluoroaniline (7.92 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (15.8 mg, 48%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:7](=C)C)[CH2:2][CH2:3][CH3:4].O=[O+][O-].[CH2:18]([OH:20])C>>[CH2:11]([O:10][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:7])[CH:18]=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: CCO
Reactant: C=C(C)C(OCCCC)OCCCC
Agent: O=[O+][O-]
Product: CCCCOC(C)(C=O)OCCCC

Procedure:
1 liter of a solution of 300 g (1.5 moles) of methacrolein di-n-butylacetal in ethanol is reacted with ozone analogously to the procedure indicated in Example 1, and is then hydrogenated. The absorption of H2 is 28.5 standard liters (84.8% of theory).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO[C:6]([C:8]1[N:12]2[C:13]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:14]=3[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH2:17][C:11]2=[N:10][N:9]=1)=[O:7]>O1CCOCC1.CO>[CH3:1][N:2]([CH3:3])[C:6]([C:8]1[N:12]2[C:13]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:14]=3[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH2:17][C:11]2=[N:10][N:9]=1)=[O:7]
Reactant: CNC
Reactant: COC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
10 ml of a 20% solution of dimethylamine in dioxane is added at 25° to a solution of 0.705 g (0.002 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxylic acid methyl ester in 10 ml of methanol. After 24 hours, the reaction mixture is concentrated by evaporation, and the residue crystallised from ethyl acetate/petroleum ether to obtain N,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 180°-181°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH2:27]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:27][CH3:26])=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CN
Reactant: Cc1nccc(-c2ccc(Cl)cc2F)c1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(Cl)cc2F)ccnc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-2-methylnicotinic acid (180 mg, 0.678 mmol) in DCM (5 mL) and DMF (0.2 mL) at 0° C., was added oxalyl chloride (0.178 mL, 2.033 mmol). The reaction mixture was stirred for 3 h at RT then diluted with DCM (5 mL) and treated with a solution of methylamine hydrochloride (457 mg, 6.78 mmol) in DCM (5 mL) cooled to 0° C. The mixture was stirred for another 1 h at RT. The solution was extracted with DCM (20 mL), washed with saturated NaHCO3 (2×10 mL) and water (20 mL); dried over Na2SO4 and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N,2-dimethylnicotinamide (50 mg, 0.179 mmol, 27% yield) as a brown gum. LC/MS, (ESI) m/z 279.2 [(M+H)+, calcd for C14H13ClFN2O 279.1]; LC/MS retention time (method D): tR=0.62 min.
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]1[N:6]=[C:7]([CH:10]([CH3:12])[CH3:11])[O:8][CH:9]=1>O1CCOCC1.O>[CH:10]([C:7]1[O:8][CH:9]=[C:5]([CH2:4][NH:2][CH3:1])[N:6]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1nc(CCl)co1
Reactant: CN
Solvent: O
Solvent: C1COCCO1
Product: CNCc1coc(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
To 40% aqueous methylamine (100 mL) was added dropwise a suspension of 4-chloromethyl-2-isopropyloxazole (4.20 g, 0.0263 mol) in p-dioxane/H2O (1:1 (v/v), 20 mL) over a 25 min period. After stirring for 45 min at ambient temperature, the volume was reduced to ca. 50 mL by rotary evaporation in vacuo, and NaCl was added. The aqueous was extracted with CHCl3 (4×100 mL), and the combined extract was dried over Na2SO4 and concentrated in vacuo. The resulting brown liquid was chromatographed on a 200 g SiO2 flash column with 2% iPrNH2 /CH2Cl2 followed by a gradient of iPrNH2 /MeOH/CH2Cl2 (0.5:2:97.5, 0.5:4:95.5). Concentration in vacuo of the product-containing fractions afforded the desired compound as a golden oil (2.89 g, 0.0187 mol, 71%): 1H NMR (CDCl3) δ1.33 (d, J=6.9 Hz, 6H), 2.46 (s, 3H), 2.99-3.14 (m, 1H), 3.64 (s, 2H), 7.42 (s, 1H). Mass spectrum: (M+H)+ =155, (M+NH4)+ =172.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:15][C:16](=[O:22])[C:17](=[CH:20][CH:21]=3)[C:18]#[N:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[K+].I[CH3:26]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([CH3:26])[C:16](=[O:22])[C:17](=[CH:20][CH:21]=3)[C:18]#[N:19])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CI
Reactant: CN1CCN(c2ccc(-c3ccc(C#N)c(=O)[nH]3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(-c3ccc(C#N)c(=O)n3C)cc2)CC1

Procedure:
A mixture of 9.1 g. of 6-[p-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile, 2.0 g. of potassium hydroxide, 5.0 ml. of iodomethane and 250 ml. of absolute ethanol is stirred and heated at reflux for 5 hours, then evaporated at reduced pressure. The residue is washed thoroughly with warm water, then dried, to give 6-[p-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinonitrile as the remaining solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:23][N:22]=1>O>[CH:3]1([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1ccc(-c2ccc(F)nc2)cc1
Reactant: OC1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ccc(OC3CCN(C4CCCC4)CC3)nc2)cc1
Temperature: 130 °C
Reaction time: 7 h

Procedure:
60% sodium hydride (13 mg) and 1-cyclopentyl-4-hydroxypiperidine (60 mg) were added to a DMF solution (3 ml) of 2-fluoro-5-[4-cyanophenyl]pyridine (56 mg), and stirred at 130° C. for 7 hours. The reaction mixture was cooled to room temperature, and water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform:methanol=9:1) to obtain the entitled compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([S:21]([OH:23])(=[O:1])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])=[C:7]([CH3:13])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cc1c(C)c2ccc(O)cc2oc1=O
Solvent: c1ccncc1
Product: O=S(=O)(O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2.3 g of 7-hydroxy-3,4-dimethylcoumarin were dissolved in 50 ml of pyridine, and 4.7 g of benzenesulfonyl chloride were added at 20° C. The mixture was stirred overnight and then poured onto 200 g of ice, and the precipitate was filtered off under suction, washed with water, recrystallized from ethanol and dried. Yield: 3.3 g (83%), mp.: 177°-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.[Cu](I)I>[Cl:1][C:2]1[C:7]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Clc1ncncc1I
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ncncc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.1 g of 4-chloro-5-iodopyrimidine, 10 mL of triethylamine, 1.2 mL phenylacetylene, 80 mg copper iodide and 160 mg of dichlorobis(triphenylphosphine was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and evaporated in vacuo. The residue was redissolved in a few mL of dichloromethane, 10 mL of triethylamine added and the mixture heated at reflux for one hour. The heterogeneous mixture was evaporated in vacuo and the residue obtained was partitioned between water and dichloromethane. A gelatinous precipitate which formed on shaking the two layers was filtered off, enabling separation of the two layers. The organic extracts were dried over sodium sulfate, filtrated and evaporated in vacuo to yield 2.5 g of a dark brown syrup. The syrup was purified by column chromatography on silica gel, twice, eluting with hexanes, 1:1 hexanes/dichloromethane, dichloromethane and finally ethyl acetate. Like fractions from dichloromethane elution were pooled, obtaining 350 mg of the product, 5-phenylethynyl-4-chloropyrimidine as an oil which solidified to white rosettes.
Reaction SMILES: [CH:1]1[C:9]2[C@H:10]3[O:15][CH2:14][CH2:13][NH:12][C@@H:11]3[CH2:16][C:7]3[C:8]=2[C:4]([NH:5][CH:6]=3)=[CH:3][CH:2]=1.[CH:17](=O)[CH3:18]>[Pd].C(O)C>[CH2:17]([N:12]1[C@@H:11]2[CH2:16][C:7]3[C:8]4[C:4]([NH:5][CH:6]=3)=[CH:3][CH:2]=[CH:1][C:9]=4[C@H:10]2[O:15][CH2:14][CH2:13]1)[CH3:18]
Reactant: c1cc2c3c(c[nH]c3c1)C[C@H]1NCCO[C@H]21
Reactant: CC=O
Agent: [Pd]
Solvent: CCO
Product: CCN1CCO[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 58.5 %

Procedure:
A suspension of trans-4,6,6a,8,9,10a-hexahydro-7H-indolo-[3,4 gh]-[1,4]-benzoxazine (650 mg, 0.03 m) acetaldehyde (260 mg, 0.006 m) and Pd/c (10%, 700 mg) in abs. ethanol (50 ml) is hydrogenated at room temperature for 4 hours. The catalyst is removed by filtration, and the solvent is removed under reduced pressure (20 mm). The oil is recrystallized from methanol to yield 430 mg of trans 4,6,6a,8,9,10a-hexahydro-7-ethyl-7H-indolo-[3,4 gh]-[1,4]benzoxazine, m.p. turns brown 200° melt 210°-213°.
Reaction SMILES: Br[CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[N:16]([CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: O=C1Nc2ccccc2CCCCC1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCCCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (14.2 g) and sodium azide (7.1 g) in dimethylsulfoxide (400 ml) is maintained at 80° under an atmosphere of nitrogen for 3 hours. The reaction mixture is poured into ice/water (1200 ml) and the suspension is stirred for 30 minutes. The solid is filtered off, washed with water (300 ml) and dried to give 3-azido-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[NH3:30]>CO.C(OCC)(=O)C>[NH2:30][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: N
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of Example 1D (1.0 g) in methanol (10 mL) and concentrated aqueous ammonia (3 mL) was heated in a sealed pressure tube to 60° C. for 16 hours, cooled to 0° C., diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: CS(N)(=O)=O.[CH3:6][NH:7][S:8]([NH2:11])(=[O:10])=[O:9].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:39][C:40]1[C:41]([O:50][CH2:51][C:52]2([C:62]#[N:63])[CH:59]3[CH2:60][CH:55]4[CH2:56][CH:57]([CH2:61][CH:53]2[CH2:54]4)[CH2:58]3)=[CH:42][C:43]([F:49])=[C:44]([CH:48]=1)[C:45]([OH:47])=O>>[Cl:39][C:40]1[C:41]([O:50][CH2:51][C:52]2([C:62]#[N:63])[CH:59]3[CH2:58][CH:57]4[CH2:56][CH:55]([CH2:54][CH:53]2[CH2:61]4)[CH2:60]3)=[CH:42][C:43]([F:49])=[C:44]([CH:48]=1)[C:45]([NH:11][S:8](=[O:10])(=[O:9])[NH:7][CH3:6])=[O:47]
Reactant: CNS(N)(=O)=O
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2Cl)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: CNS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with methyl sulfamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following trituration with diethyl ether (10 mL) as a colorless powder (0.073 g, 52%): 1H NMR (300 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.73-7.66 (m, 2H), 7.34 (d, J=12.2 Hz, 1H), 4.54 (s, 2H), 2.53 (d, J=4.6 Hz, 3H), 2.15-2.07 (m, 4H), 1.97-1.78 (m, 6H), 1.70-1.60 (m, 4H); MS (ES−) m/z 454.1, 456.1 (M−1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28].C(OCC)(=O)C>N1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:18]=1[OH:19])[C:8](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: NNC(N)=O
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(=NNC(N)=O)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
1.60 g of 3,5-di-t-butyl-4-hydroxybenzophenone and 0.67 g of semicarbazide hydrochloride were dissolved in 12 ml of pyridine, and the solution was refluxed for 6 hours. After the reaction, ethyl acetate was added to the reaction mixture, and the mixture was washed with 5% hydrochloric acid and water and dried. The solvent was removed by concentration, and the residue was chromatographed on a silica gel column and recrystallized from diethyl ether to give 3,5-di-t-butyl-4-hydroxybenzophenone semicarbazone.
Reaction SMILES: C1C=C(CC[CH:9]([C:17]2[C:22]([OH:23])=CC=CC=2)[C:10]2[C:15]([OH:16])=CC=CC=2)C(O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:16][CH:15]1[CH2:10][CH2:9][CH2:17][CH2:22][O:23]1
Reactant: Oc1ccccc1CCC(c1ccccc1O)c1ccccc1O
Reactant: C1=COCCC1
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A suspension of triphenol 3 (164 g, 0.672 mol) in 3, 4dihydro-2H-pyran (600 mL) (available from Aldrich Chemical Company Inc., Milwaukee, Wis.) was treated with p-toluenesulfonic add monohydrate (2×10 mg) at 0° C. The reaction mixture was stirred for 1.5 h at 0° C. and then for 1 h after removing the ice bath (the reaction was monitored by TLC; p-toluenesulfonic acid monohydrate was added until starting material and monotetrahydropyranyl ether had disappeared). The mixture was then treated with saturated sodium bicarbonate (250 mL) and ethyl acetate (1 L). The organic phase was washed with saturated sodium bicarbonate (250 mL) and brine (250 mL), dried over magnesium sulfate and evaporated under reduced pressure. The crude compound was triturated with hexanes (2 L) for 3 h with stirring. The resulting suspension was left to stand at 0° C. for 5 h and then at -20° C. for 18 h. The solid was filtered and treated again with hexanes (1 L) with stirring for 1 h to give compound 4 which was filtered and dried (190 g, 69%), mp 109-112° C.: 1H-NMR δ (300 MHz: CDCl3), 1.5-2.1 (12H, m, O CH--CH2 --CH2 --CH2 --CH2 --O), 3.55-3.65 (2H, m, O--CH--CH2 --CH2 --CH2 --CH2O), 3.75-3.95 (2H, m, O--CH--CH2 --CH2 --H2 --CH2O), 4.16 (2H, s, Ph--CH2C=O), 5.40 (1H, t, J=3 Hz, O--CH--CH2 --CH2 --CH2 --CH2 --O), 5.49 (1H, t, J=3 Hz, O--CH--CH2 --CH2 --CH2 --CH2 --O), 6.55 (1H, dd, J=2.5 Hz and 8.5 Hz, CH phenyl), 6.61 (1H, d, J=2.5 Hz, CH phenyl), 7.03 and 7.17 (2H, AB system, J=8.5 Hz, CH phenyl), 7.77 (1H, d, J=8.5 Hz, CH phenyl), 12.60 (1H, s, Ph OH).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH-:12].[Cs+]>C(OCC)(=O)C.CCCCCCC>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:12]
Reactant: Brc1ccc2ccccc2c1
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Oc1ccc2ccccc2c1
Yield: 88 %

Procedure:
Following general operating mode B, 2-bromonaphthalene (207 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a white solid with a yield of 88% (eluent: ethyl acetat/heptane 20:80).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[NH4+].[Cl-]>CO.O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[C:14]([NH2:15])=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2c(cc1N)OCCO2
Yield: 90.5 %

Procedure:
A mixture of 12.0 g (50.2 mmol) of 7-nitro-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid methyl ester, 11.2 g (201 mmol) of powdered Fe and 13.3 g (257 mmol) of NH4Cl in 175 ml of MeOH and 70 mL of H2O was refluxed for 5.5 h. An additional 11.2 g of Fe and 13.3 g of NH4Cl was added and the mixture was heated for 5.5 h more. Finally, 5.5 g of Fe and 6.5 g of NH4Cl was added and the mixture was heated for 4 h. The cooled reaction was filtered through Celite, the pad was washed well with MeOH and the filtrate and washings were combined. The solvent was removed and the residue was slurried in H2O and collected. The crude product was filtered through silica (CHCl3) to give 9.5 g of the title compound as tan crystals: mass spectrum (electrospray, m/e): M+H 209.9.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:23]([C:22]1[CH:21]=[C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: N#Cc1cccc(N)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c1
Yield: 40 %

Procedure:
Prepared from VII and 3-aminobenzonitrile. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 40%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3240, 3171, 3088, 2228, 1623, 1591, 1555, 1509, 1465, 1393, 1273, 1229, 1149, 969, 919, 825; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.43 (s, 1H), 7.74 (m, 2H), 7.55-7.53 (m, 3H); HRMS calcd for C17H9N6S (M+H+): 329.0609, found 329.0600.
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=12)([O-:5])=[O:4]>ClCCl>[Br:1][C:14]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[N+:3]([O-:5])=[O:4])[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])ccnc21
Reactant: BrBr
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(Br)c2c([N+](=O)[O-])ccnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 18 μl (6.13 mmol) of bromine are added dropwise to a solution of 100 mg (340 μmol) of 4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine in 10 ml of dichloromethane. After 1 h of stirring at 0° C. and 1 h of stirring at RT, the reaction solution is filtered through an Extrelut silica gel cartridge, the cartridge is washed with a little dichloromethane/methanol and the filtrate is concentrated under reduced pressure. The residue is purified by preparative RP-HPLC.