Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36](=[O:39])(=[O:38])[NH2:37])=[CH:26][C:25]=2[F:40])[C:7](=[O:22])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[Cl:21])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](O)=[O:45].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36](=[O:38])(=[O:39])[NH:37][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=3[Cl:41])=[CH:26][C:25]=2[F:40])[C:7](=[O:22])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[Cl:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 65 %

Procedure:
Following the procedure of Example 51, 5-n-butyl-2-[2-chloro-5-(propionylamino)phenyl]-2,4-dihydro-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step E) was reacted with 2-chlorobenzoic acid (2 equivalents), CDI (2 equiv), and DBU (2 equiv). Purification of the crude product by flash chromatography on silica gel (gradient elution with 1-5% MeOH in CH2Cl2) gave a 65% yield of the title compound as a white solid, mp >152° C. (gradual); homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 762 (M+K)+.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.[CH3:12][S:13][CH2:14][CH:15]=[CH:16][N:17]1CCCC1.C([O-])(=O)C.[NH4+]>C(#N)C>[CH3:12][S:13][CH2:14][C:15]1[CH:4]=[CH:5][C:6]([C:7]([F:8])([F:9])[F:10])=[N:17][CH:16]=1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CSCC=CN1CCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: CSCc1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a dry 1 L round bottom flask equipped with a magnetic stir bar, liquid addition funnel, thermometer, and nitrogen inlet were added 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (M) (67.4 g, 401 mmol) and 133 mL of anhydrous acetonitrile, and the resulting solution was cooled to 0° C. in an ice bath. To this solution was added 1-[3-(methylthio)prop-1-enyl]pyrrolidine (L) (63.0 g, 401 mmol, dissolved in 50 mL of anhydrous acetonitrile) dropwise via the addition funnel at a rate which maintained the reaction temperature at 0-7° C. The ice bath was removed and the resulting burgundy solution was warmed to room temperature and stirred for 2 hours. Ammonium acetate (46.3 g, 601 mmol) was added and the reaction was heated to reflux and stirred for 5 hours, and then stirred at room temperature for 16 hours. The acetonitrile was evaporated on the rotary evaporator and the residue was dissolved in 1 L of Et2O, washed with water (3×200 mL), dried (Na2SO4), filtered, and the Et2O removed on the rotary evaporator to give 83.4 g of the crude pyridine as a dark-red oil. Flash chromatography (SiO2, 25→70% EtOAc/Hexanes) afforded 70.8 g (85%) of 5-[(methylthio)methyl]-2-(trifluoromethyl)pyridine (N) as an orange oil. 1H NMR (CDCl3) δ 8.64 (d, 1H), 7.86 (dd, 1H), 7.66 (d, 1H), 3.73 (s, 2H), 2.02 (s, 3H). GC-MS (EI) m/z 207 (M+).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:21][C:17]1[CH:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(OCC)c1cccc(-c2cccc(C)c2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)c1cccc(-c2cccc(CBr)c2)c1
Temperature: 25 °C

Procedure:
To the compound of Step 2 (0.122 g, 0.400 mmol) in CCl4 (5 mL) were added NBS (0.050 g, 0.480 mle) and a catalytic amount of benzoyl peroxide. The reaction mixture was refluxed under light for 2 h. The reaction was cooled to room temperature, filtered and evaporated. The title compound was obtained after purification by flash chromatography. (0.150 g).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH2:24])=[C:22]([CH3:28])[CH:21]=1>>[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH:24][C:2]2[CH:17]=[C:6]3[C:7]4[C:12]([CH2:13][CH2:14][N:5]3[C:4](=[O:18])[N:3]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=4)=[C:22]([CH3:28])[CH:21]=1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Cc1cc(Cl)cc(C)c1N
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(C)cc(Cl)cc2C)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 4-Chloro-2,6-dimethyl-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 8.73 (br, 1H), 7.72 (br, 1H), 7.19 (s, 2H), 7.03-6.95 (2H), 6.36 (br, 1H), 3.95 (t, 2H), 3.85 (s, 3H), 2.96 (t, 2H) and 2.18 (s, 6H); MS (ESI) (M+H)+ 382.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].O[C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=1.S(=O)(=O)(O)O>C(O)C.O>[Cl:3][C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][O:7][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=1
Reactant: OCCc1ccc(O)cc1
Reactant: OCc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCc1ccc(OCc2ccc(Cl)cc2Cl)cc1

Procedure:
2.8 g. of sodium hydroxide in 10 ml. of water and 13.6 g. of 2,4-dichlorobenzyl alcohol are added to 8 g. of 4-hydroxyphenethyl alcohol in 80 ml. of ethanol. After refluxing the solution for 1.5 hours, the mixture is acidified with dilute sulfuric acid and extracted with methylene chloride. Drying and evaporation of the solvent yields the crude product at 100°-130° (air bath temperature)//0.02 torr by distillation with the use of a bulb tube. From cyclohexane, 14.5 g. of 4-(2,4-dichlorobenzyloxy)-phenethyl alcohol is obtained, m.p. 55°. The alcohol is converted, by 10 minutes of heating with thionyl chloride, into the [4-(β-chloroethyl)-phenyl]-(2,4-dichlorobenzyl)-ether and added to a solution of sodium imidazole, obtained by reacting 2 g. of imidazole with 1.04 g. of 80% strength sodium hydride - oil suspension in 30 ml. of dimethylformamide; the mixture is agitated for 6 hours at 100°-120° . The product is worked up as indicated in Example 56.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.CN(C)[CH:22]=[O:23].O>C(OCC)C>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:22]=[O:23])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(OCC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.4 g of 2-bromobenzaldehyde diethyl acetal in 200 ml of dry diethyl ether at −65° C. was added 27.5 ml of a 1.6 M solution of butyllithium in hexanes. The solution was stirred at this temperature for 30 min. then slowly warmed to −40° C. when 3.4 ml of dimethylformamide was added dropwise. The reaction was warmed to room temperature then 100 ml of water was added and the organic layer was separated. The aqueous layer was extracted with two 100 ml portions of ether and the combined organic extracts were dried over sodium sulfate and evaporated to give 8.5 g of 2-formylbenzaldehyde diethylacetal as an oil; 1H-NMR (200 MHz, CDCl3) d 5.06 (CHOEt).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][O:21][CH2:22][CH3:23])[N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=3[C:4]=2[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[C:14]1[CH2:20][O:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCn1c(COCC)nc2c(N)nc3ccc(Br)cc3c21
Reactant: OB(O)c1ccccc1
Product: CCCCn1c(COCC)nc2c(N)nc3ccc(-c4ccccc4)cc3c21

Procedure:
8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (10% methanol in CH2Cl2) followed by recrystallization from isopropanol afforded 1-butyl-2-ethoxymethyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, m.p. 186-187° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: C1=COCCC1
Reactant: OCCOc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(OCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 12.0 g (55.4 mmol) 2-(4-bromophenoxy)ethanol, 100 ml dry methylene chloride and 5.1 g (60.9 mmol) dihyropyran is added, at RT, 0.42 g (2.2 mmol) p-toluenesulfonic acid.water. The mixture is stirred for 3 days at RT, after which 50 ml methylene chloride, 50 ml water and 10 ml aqueous 15% potassium carbonate are added. The organic phase is separated and washed with water (60 ml) and with saturated aqueous sodium chloride, and is then dried over calcium sulfate. Solvent is removed by rotary evaporation to yield 4-(2-tetrahydropyranyloxyethoxy)bromobenzene.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24](C#N)[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:30][C:31]([F:58])([F:57])[O:32]C1C=C(C2N=C(OS(C(F)(F)F)(=O)=O)C=C3C=2N=CC=C3)C=CC=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:32][C:31]([F:58])([F:57])[F:30])[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Oc1cc2cccnc2c(-c2cccc(OC(F)(F)F)c2)n1)C(F)(F)F
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Product: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(OC(F)(F)F)c3)n2)CC1

Procedure:
This compound is prepared in an analogous way to compound 4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester from trifluoromethanesulfonic acid 8-(3-trifluromethoxyphenyl)-[1,7]naphthyridin-6-yl ester. Purification is by chromatography followed by trituration with ether to yield a white solid. MS (AP+) 445
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O>CO>[CH:15](=[N:10][NH:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:4][CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C(NN=Cc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution (50 ml) of 4-trifluoromethylbenzohydrazide (3.06 g) and benzaldehyde (1.52 ml) in methanol was added dropwise conc. sulfuric acid (0.5 ml), and this mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was washed with hexane-ethanol (1:1, volume ratio) and recrystallized from ethanol to give N′-benzylidene-4-trifluoromethylbenzohydrazide (3.23 g, yield 74%) as colorless needle crystals. melting point: 216–217° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH2:27]Cl)=[O:24])=[C:16]3[N:15]=2)[C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[N:6][CH:7]=1)[O:8][CH2:27][CH2:26][O:25][C:23](=[O:24])[C:22]1=[C:16]3[N:15]=[C:14]([CH:19]=[CH:18][N:17]3[N:20]=[CH:21]1)[N:10]1[C@@H:9]2[CH2:13][CH2:12][CH2:11]1
Reactant: O=C(OCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OCCOc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 90 °C

Procedure:
A mixture of (R)-2-chloroethyl 5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (54 mg, 0.133 mmol) and Cs2CO3 (217 mg, 0.665 mmol) in DMF (6 mL) was heated at 90° C. overnight. The reaction was filtered (GF/F paper) and directly purified by reverse phase column chromatography (Biotage SP4 system C18 25+M, 5 to 60% acetonitrile/water) to yield a mixture of desired product and impurities. This mixture was treated with a second column chromatography on Biotage SNAP KP-Sil 10 g, eluting with 10% hexanes/EtOAc to give the pure title product as a white solid (11 mg, 22% yield). MS (apci pos) m/z=370.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][N:22]([CH:25]=[O:26])[CH2:21][CH2:20]2)[C:8]1=[O:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:40][C:41]#[N:42]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:40][C:41]#[N:42])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][N:22]([CH:25]=[O:26])[CH2:21][CH2:20]2)[C:8]1=[O:27]
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCC#N)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 60.5 %

Procedure:
0.17 g of 4-[3-(3,4-dimethoxybenzyl)-6-hydroxy-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde obtained in stage 1.8 and 0.25 g of Cs2CO3 in 3 ml of DMF are stirred for 15 min at AT. 0.056 g of bromoacetonitrile is added and the reaction mixture is subsequently irradiated under a microwave field at 100° C. for 15 min. It is filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an MeOH/DCM mixture, (1/99, v/v) as far as (4/96, v/v), to give 0.112 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1)[O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH3:13])[CH:7]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:16]3[CH:15]=[CH:14][C:4]([O:5][C:6]4[CH:7]=[C:8]([CH3:13])[N:9]=[C:10]([CH3:12])[CH:11]=4)=[CH:3][C:2]=3[F:1])=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: Cc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)c(F)c2)cc(C)n1

Procedure:
To a solution of intermediate 18 (1.05 mmol) in 1,4-dioxane (4.5 ml) and a saturated solution of NaHCO3 (4.5 ml) was added intermediate 5 (0.22 g, 0.892 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.13 mg, 0.114 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with EtOAc, and then it was washed with water, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 5% as eluent). The desired fractions were collected and evaporated in vacuo to give a residue that was further purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 8 that was precipitated from diisopropylether (0.176 g, 51%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:10]([CH:21]([CH:33]([CH3:35])[CH3:34])[C:22]([NH:24][O:25]CC2C=CC=CC=2)=[O:23])[C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].[O-]S([O-])(=O)=O.[Ba+2].CO>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:10]([CH:21]([CH:33]([CH3:34])[CH3:35])[C:22]([NH:24][OH:25])=[O:23])[C:9]1=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)NOCc2ccccc2)C(C)C)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: COc1ccc(C2CN(Cc3ccccc3)C(=O)N2C(C(=O)NO)C(C)C)cc1
Reaction time: 4 h
Yield: 62.5 %

Procedure:
2-(3-Benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-benzyloxy-3-methylbutyramide (120 mg; 0.24 mmol) was introduced into methanol (10 ml), and Pd/BaSO4 (50 mg) was added. The mixture was hydrogenated with H2 (1 atm) at RT for 4 h. The reaction mixture was then filtered through kieselguhr, the residue was washed with methanol, and the filtrate was concentrated in a rotary evaporator. Purification by preparative HPLC resulted in 2-(3-benzyl-5-(4-methoxyphenyl)-2-oxoimidazolidin-1-yl)-N-hydroxy-3-methylbutyramide (60 mg, 0.15 mmol). MS: 398.15 (M+H); Rt: 1.31 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[N:11]([CH3:19])[N:10]=1.[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[S:15][C:16]([Br:20])=[CH:17][CH:18]=2)[N:11]([CH3:19])[N:10]=1
Reactant: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1cccs1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2c(Cl)cccc2Cl)nc1-c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2,6-dichlorophenyl)-5-(thien-2-yl)-1-methyl-[1,2,4]triazole (75 mg, 0.242 mmol) and bromine (39 mg, 0.242 mmol) were combined in glacial acetic acid (3mL) and the mixture was stirred overnight at room temperature, then heated to 95° C. for five hours. The reaction mixture was poured into a saturated sodium bicarbonate solution, extracted with ether, and dried over magnesium sulfate. Chromatography (SiO2, 25% Hex-CH2Cl2) delivered the title product as a waxy white solid. MP 130-132° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[Mg].[O:8]1[CH2:11][CH2:10][C:9]1=[O:12]>C1COCC1.II>[OH:8][CH2:11][CH2:10][C:9]1([OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCBr
Reactant: O=C1CCO1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OCCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
A solution of 1,4-dibromobutane (10 g, 46 mmol) in THF (100 mL) was treated with magnesium (2.81 g, 116 mmol) and I2 (100 mg). The mixture was stirred at room temperature for 3 hours a solution of oxetan-2-one (3.34 g, 46.3 mmol) in THF (25 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours then quenched with saturated aqueous NH4Cl and extracted with isopropanol/CH2Cl2 (1:3) (2×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by distillation (95-100° C. at 0.6 Ton) to provide 1.1 g (18%) of the title compound. MS (DCI/NH3) m/z 148 (M+NH4)−.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:38]3[CH:37]=[C:36]4[C:31]([N:32]=[CH:33][CH:34]=[N:35]4)=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:39]>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:35]1[C:36]2[C:31](=[CH:30][C:29]3[O:28][CH2:27][C:20]4([C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18][C:19]4=[O:39])[C:38]=3[CH:37]=2)[N:32]=[CH:33][CH2:34]1
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1cc3nccnc3cc12
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)N(Cc1ccccn1)CC=N3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7H-spiro[furo[2,3-g]quinoxaline-8,3′-indolin]-2′-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one was obtained (93%) as a pale orange solid: mp 232-233° C.; 1H NMR (300 MHz, CDCl3) δ8.64 (m, 1H), 8.59 (d, J=1.5 Hz, 1H), 8.44 (d, J=1.5 Hz, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.77-7.67 (m, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.28-7.17 (m, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 5.56 (d, J=16.5 Hz, 1H), 5.25 (d, J=9.0 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.91 (d, J=16.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ177.2, 162.5, 155.9, 149.4, 144.9, 142.3, 142.1, 139.8, 139.8, 136.9, 132.6, 132.4, 128.8, 123.3, 123.2, 122.6, 121.9, 121.4, 116.6, 109.6, 82.6, 57.7, 46.5; MS (ES+) m/z 381.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)c1c(N)sc2ccc(C)cc12
Solvent: CS(C)=O
Product: COC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccc(C)cc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using methyl 2-amino-5-methylbenzo[b]thiophene-3-carboxylate (3.11 g), 2,4-difluoronitrobenzene (1.54 ml) and dimethyl sulfoxide (30 ml), methyl 2-(5-fluoro-2-nitroanilino)-5-methylbenzo[b]thiophene-3-carboxylate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C@@H:30]([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C@@H:30]([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and (S)-7-chlo-ro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.