Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)#[N:2].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][N:19]2[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]2=[O:26])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][N:19]2[C:20](=[O:26])[CH:21]=[CH:22][C:23]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=3)=[CH:24]2)=[CH:16][CH:15]=1
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Product: N#CCc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Yield: 100 %

Procedure:
According to Scheme 3 Method A: The title compound was synthesized as described in Example 2 Step 2 using 4-(cyanomethyl)phenyl boronic acid (1.5 eq, 0.50 mmol, 80.9 mg) and 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 0.33 mmol, 0.10 g, Example 2 Step 1) as substrates. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt to afford 2-(4-(1-(4-chlorobenzyl)-1,6-dihydro-6-oxopyridin-3-yl)phenyl)acetonitrile as a yellow solid (0.33 mmol, 110 mg, 98%).
Reaction SMILES: [Cl-].[NH4+:2].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11]>O.CO.[Fe]>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:2])=[CH:6][C:5]=1[O:10][CH3:11]
Reactant: [NH4+]
Reactant: COc1ccccc1Br
Agent: [Fe]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COc1cc(N)ccc1Br
Temperature: 75 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A suspension of iron powder (40.8 g, 0.730 mol), ammonium chloride (64.7 g, 1.21 mol) and 2-bromoanisole (50 g, 0.215 mol) in water (1.5 L) and MeOH (1 L) was stirred overnight at 75° C. The solid was filtered off and the liquid was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 43.1 g of the title compound were obtained. Brown solid, ISP-MS: m/e=203.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:1][C:2]1[N:11]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:26](=[O:27])[C:25]3[CH:36]=[CH:37][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:35][CH:34]=2)[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To a solution of 8-chlorotheophylline (2.15 g) in DMF (20 ml) was added potassium carbonate (1.66 g) as well as 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as white powder (3.34 g, 75%). 1H-NMR (CDCl3) 6: 3.41(3H,s), 3.57(3H,s), 5.64(2H,s), 7.41-7.52(4H,m), 7.68-7.80(4H,m).
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[CH3:22][C:23](=[O:26])[C:24]#[CH:25]>C1(C)C=CC=CC=1>[C:23]([C:24]1[CH:25]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:3](=[O:2])[N:7]2[C:6]=1[C:11]1[S:12][CH:13]=[CH:14][C:10]=1[CH2:9][CH2:8]2)(=[O:26])[CH3:22]
Reactant: Oc1c(-c2cccc(F)c2)sc2[n+]1CCc1ccsc1-2
Reactant: C#CC(C)=O
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2

Procedure:
A solution of 0.303 g of 5,6-dihydro-3-hydroxy-2-(m-fluorophenyl)-thiazolo-[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) and 0.145 ml of 3-butyn-2-one in 5 ml of toluene was heated under reflux for 1 hour. The solvent is evaporated in vacuo and the residue is chromatographed over silica gel with toluene/ethyl acetate (1:1). After recrystallization from ethanol, there was obtained 10-acetyl-4,5-dihydro-8-(m-fluorophenyl)-7H-thieno[2,3-a]quinolizin-7-one of m.p. 109°-110°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([CH2:26][CH2:27][CH2:28]C2C=CC=CC=2)=[C:17]([CH3:25])C=[CH:19][C:20]=1S([O-])(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2>C(#N)C>[C:36]12([NH:35][CH2:19][CH2:20][CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]3[CH:17]=[CH:25][CH:28]=[CH:27][CH:26]=3)[CH2:37][CH:38]3[CH2:44][CH:42]([CH2:41][CH:40]([CH2:39]3)[CH2:45]1)[CH2:43]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)[O-])c(-c2ccccc2OCc2ccccc2)c1CCCc1ccccc1
Solvent: CC#N
Product: c1ccc(COc2ccccc2C(CCNC23CC4CC(CC(C4)C2)C3)c2ccccc2)cc1

Procedure:
This compound was similarly prepared from the toyslate (XXIX) of Example 4d) and 1-aminoadamantane. It was used as start material in Example 7q). The hydrochloridesemihydrate was prepared in acetonitrile and melted at 225° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[S:21][C:22]([S:26](Cl)(=[O:28])=[O:27])=[C:23]([CH3:25])[N:24]=1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:26]([C:22]2[S:21][C:20]([CH3:19])=[N:24][C:23]=2[CH3:25])(=[O:28])=[O:27])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Product: Cc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 2,4-dimethylthiazole-5-sulfonyl chloride (0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,4-dimethylthiazole-5-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.3 (s, 3H), 2.6 (s, 3H), (s, 1H), 5.9 (dt, 1H), 7.1 (q, 1H), 7.2 (d, 1H), 73 (m, 1H), 7.4 (d, 1H), 7.4 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Br[CH2:12][CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:12]([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)=[CH:13][CH2:14][CH3:15]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC=COc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
A 500 ml flask equipped with a mechanical stirrer, condenser, thermometer, and heating mantle was charged with p-nitrophenol (30.0 g, 216 mmol), 4-bromo-1-butene (29.1 g, 216 mmol), potassium carbonate (32.8 g, 237 mmol) and DMF (300 ml). The reaction mixture was heated to reflux and stirred for 48 hours. It was then cooled and solvent removed under reduced pressure. The residue was dissolved in 250 ml of methylene chloride and washed repeatedly with water to remove traces of DMF. The methylene chloride layer was dried (MgSO4), filtered, and solvent removed under reduced pressure. The product was used without further purification for the next step. Yield=7.0g (17%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([NH:2][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:10][CH2:11]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCOC(=O)N1CCC(N(CCN)CCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC(N(CCNC(=O)c2ccccc2)CCc2ccc(Cl)cc2)CC1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Allyl 4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate hydrochloride obtained in Step 2 was suspended in dichloromethane (4 mL/mmol), the suspension was cooled to −15° C. and DIPEA (2.2 equiv) followed by benzoyl chloride (1.05 equiv) were added dropwise over 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. After 2 h TLC revealed no presence of starting material. The reaction mixture was diluted with EtOAc (10 mL/mmol of starting material), washed with 1 M NaOH (2×), water (2×) and brine (2×) and dried over anhydrous MgSO4. After filtration of the drying agent the solvent was stripped off and the crude product was purified by column chromatography.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:34]=[CH:33][C:8]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[NH:18][C:19](=[O:32])[CH2:20][NH:21]C(=O)OCC2C=CC=CC=2)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCOCC.[BrH:40].CC(O)=O>>[BrH:40].[NH2:21][CH2:20][C:19]([NH:18][C@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][C:9](=[O:10])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:34][CH:33]=1)=[O:32]
Reactant: NS(=O)(=O)c1ccc(C(=O)N[C@H]2CCCC[C@H]2NC(=O)CNC(=O)OCc2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NCC(=O)N[C@H]1CCCC[C@H]1NC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h

Procedure:
The material from above benzyl (cis)-2-[(2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethylcarbamate (217 mg) was dissolved in 30% HBr/AcOH (5 mL) at rt. After 1 h, Et2O was added and the solid was collected to give N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamide hydrogen bromide. MS found: (M+H)+=355.2.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[N:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)=[N+:11]=[N-:12].[OH-].[Na+]>C(O)C.O>[N:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:7]2[CH2:8][CH:3]([O:2][CH3:1])[CH2:4][C:5](=[CH:17][C:16]3[CH:19]=[CH:20][C:13]([N:10]=[N+:11]=[N-:12])=[CH:14][CH:15]=3)[C:6]2=[O:9])=[CH:15][CH:14]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Reactant: COC1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC1CC(=Cc2ccc(N=[N+]=[N-])cc2)C(=O)C(=Cc2ccc(N=[N+]=[N-])cc2)C1
Yield: 15.6 %

Procedure:
In 100 ml of ethanol were dissolved 10 g of 4-methoxycyclohexanone and 30 g of para-azidobenzaldehyde, after which a solution of 1 g of sodium hydroxide in 1 ml of water was added, and the resulting mixture was subjected to reaction in a brown flask at room temperature for 2 days. The crystals formed were separated by suction filtration, washed with ethanol, and then recrystallized from methyl Cellosolve to obtain 4.7 g of yellow crystals having a decomposition point of 145° to 150° C. (differential thermal analysis, the rate of heating: 5° C./min).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]([CH:14]1[CH2:17][N:16]([C:18](=[O:38])/[CH:19]=[CH:20]/[C:21]2[CH:22]=[C:23]3[C:34](=[N:35][CH:36]=2)[NH:33][C:32](=[O:37])[C:25]2([CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:24]3)[CH2:15]1)(=O)[CH3:12]>CO>[CH3:31][N:28]1[CH2:29][CH2:30][C:25]2([CH2:24][C:23]3[C:34](=[N:35][CH:36]=[C:21](/[CH:20]=[CH:19]/[C:18](=[O:38])[N:16]4[CH2:15][CH:14](/[C:11](=[N:10]/[O:9][CH2:2][C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)/[CH3:12])[CH2:17]4)[CH:22]=3)[NH:33][C:32]2=[O:37])[CH2:26][CH2:27]1
Reactant: NOCc1ccccc1
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Agent: Cl
Solvent: CO
Product: C/C(=N\OCc1ccccc1)C1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reaction time: 8 h

Procedure:
O-benzylhydroxylamine hydrochloride (13.5 mg, 0.08 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-1′-methyl-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (23.0 mg, 0.06 mmol) in methanol (1.5 mL) at room temperature. The reaction mixture was stirred overnight. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol (9:1) as eluent. The title product was obtained as a pink solid (9 mg, 31%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:35]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:39]([CH:35]3[CH2:38][CH2:37][CH2:36]3)(=[O:41])=[O:40])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)C1CCC1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1
Reaction time: 8 h
Yield: 92.2 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. Cyclobutanesulfonyl chloride (0.253 g, 1.637 mmol) was added. The solid immediately dissolved. The mixture was stirred overnight, then it was diluted with DCM and washed with brine (1×50 mL). The organic phase was collected, dried on MgSO4 and the volatiles were evaporated under reduced pressure, yielding the product as a pale yellow solid (731.7 mg, 1.51 mmol, 92%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:22]=3)[CH:17]=[CH:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C1COCC1>[Br:1][C:17]1[C:18]2[C:23](=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[N:15]([C:12]2[CH:11]=[CH:10][N:9]=[CH:14][CH:13]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ccn(-c4ccncc4)c3c2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(Br)cn(-c4ccncc4)c3c2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
N-Bromosuccinimide (64.4 mg, 0.36 mmol) was added to a mixture solution of tert-butyl 4-(1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (137 mg, 0.36 mmol) in THF (12 mL) at −78° C. After stirring at −78° C. for 2 hours, the mixture was further stirred at 0° C. for 1 hour and then pyridine (88 μL, 1.09 mmol) was added. After filtering using a diatomite pad, the solution was adsorbed by adding silica gel. Purification by chromatography (silica gel, EA:Hx=4:1) yielded the target compound (49.1 mg, 30%) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccc(Oc2ncccn2)c1
Yield: 70.9 %

Procedure:
EX-605A) A slurry of 3-hydroxybenzaldehyde (1.22 g, 10 mmol), 2-chloropyrimidine (1.14 g, 10 mmol) and K2CO3 (1.65 g, 12 mmol) in DMSO (20 mL) was heated to 100° C. for 1 h. The cooled mixture was poured into water and extracted with Et2O. The organic layer was washed with 2.5 N NaOH, 1 N HCl, saturated NaHCO3 and brine, dried (MgSO4) and evaporated to yield 1.42 g (71%) of the desired 3-(2-pyrimidinyl-oxy)benzaldehyde product as a white solid which was used without further purification. 1H NMR (C6D6) δ 7.12 (t, 1H), 7.54 (m, 1H), 7.66 (t, 1H), 7.78 (m, 1H), 7.83 (m, 1H), 8.64 (d, 2H), 10.05 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[Br:19]Br.[OH-].[Na+]>CC(OC)(C)C.C(O)(=O)C>[Br:19][CH2:17][C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[Cl:1])=[O:18]
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: O=C(CBr)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (1000 g) was dissolved in MTBE (5000 mL) and a solution of bromine (563 g) in glacial acetic acid (400 mL) was added dropwise at room temperature. After completion of the addition the mixture was stirred for 1 h at room temperature and the pH was adjusted to 7-8 by addition of 10% NaOH solution. The organic layer was separated, extracted twice with MTBE and the combined organic phases were washed with sat. NaHCO3 solution (1×) and brine (2×). The solvent was evaporated and the crude product was used directly in the next step.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:26](Cl)(Cl)=[O:27]>ClCCl>[CH2:1]([N:8]1[CH2:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[O:11][S:26]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O[C@H](CNCc1ccccc1)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S1O[C@@H](c2ccc(Cl)cc2)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
To a suspension of (S)-2-benzylamino-1-(4-chlorophenyl)ethanol (15.76 g, 60.21 mmol) and triethylamine (33.6 ml, 241 mmol) in dichloromethane (300 ml) was added a solution of thionyl chloride (4.83 ml, 66.2 mmol) in dichloromethane (20 ml) at −78° C. over 20 min. The resulting suspension was stirred at −78° C. for 20 min and at 0° C. for additional 20 min. The reaction mixture was partitioned between ether and water, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10-20% ethyl acetate-hexane) to afford (2RS,5S)-3-benzyl-5-(4-chlorophenyl)-1,2,3-oxathiazolidine 2-oxide (16.2 g 87.4%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH3:9])=[CH2:5])[CH3:2].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[Cl:30][CH:31](Cl)[F:32]>O.CCOCC>[CH2:6]([C:4]1([O:3][CH2:1][CH3:2])[CH2:5][C:31]1([Cl:30])[F:32])[CH2:7][CH2:8][CH3:9]
Reactant: C=C(CCCC)OCC
Reactant: FC(Cl)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCC1(OCC)CC1(F)Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 61.0 g. of 2-ethoxy-1-hexene, 135 ml. of 13.5 M potassium hydroxide and 217 g. of "18-crown -6" ether at -15° C. is added dropwise over 30 minutes at 0°, a 90 ml. portion of dichlorofluoromethane. After the addition, the mixture is placed in an ice bath. An exotherm raises the temperature to 20° C., whereupon the mixture is placed in a dry-ice/carbon tetrachloride bath to maintain the temperature at -5° C. to 0° C. After three hours at this temperature, the reaction mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, then brine, dried over potassium carbonate and concentrated in vacuo to an oil. This oil is distilled through a 6 inch Vigreux column to provide 82 g. of the desired compound as a colorless liquid, b.p. 70°-71° C., 16 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccn1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(Oc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a stirred solution of 4-bromophenol (200 mg) in DMF (3 mL) was added NaH (60% in oil, 46.2 mg) at room temperature. The mixture was stirred for 30 min, and 2-chloropyridine (131 mg) was added. The mixture was exposed to microwave irradiation at 230° C. for 1 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (76 mg).
Reaction SMILES: [Na].[F:2][C:3]([F:24])([F:23])[C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][C:8]([CH:10]([CH2:17][C:18]#[N:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>CO>[F:2][C:3]([F:23])([F:24])[C:4]1[CH:5]=[C:6]([C:7]2[C:8](=[O:9])[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][C:18]=2[NH2:19])[CH:20]=[CH:21][CH:22]=1
Reactant: N#CCC(C(=O)Cc1cccc(C(F)(F)F)c1)c1ccccc1
Agent: [Na]
Solvent: CO
Product: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)C1
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A dry 500-ml, three-neck, round-bottomed flask equipped with a mechanical stirrer, addition funnel and a reflux condenser bearing a nitrogen inlet tube was charged with 75 ml of methanol and 4.0 g of sodium. After all the sodium had reacted, a solution containing 38.4 g of [a-(3-trifluoromethyl-benzylcarbonyl)benzyl]acetonitrile in 75 ml of methanol was added rapidly dropwise while the reaction mixture was stirred at reflux. Reflux was continued for about 16 hours after which time the reaction mixture was concentrated in vacuo. The residue was dissolved in diethyl ether and washed once with 10% hydrochloric acid. The aqueous phase was back extracted (2X) with ether and the combined organic layers were dried over magnesium sulfate and concentrated to yield a red paste. The paste was triturated with ether to yield 7.8 g of the title compound as a pale yellow solid, (MP 205° to 206° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12].[OH-].[K+].C(O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=2[NH2:12])=[CH:4][CH:3]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: Fc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(F)cc1

Procedure:
A mixture of 29.7 g. (0.231 mole) of 4-fluorothiophenol, 41 g. (0.238 mole) of 2-chloro-5-nitroaniline and 14.9 g. (0.266 mole) of potassium hydroxide in 500 ml. of 95 percent aqueous ethanol is heated to its reflux temperature and maintained at reflux for one hour, then cooled with an ice bath. Some crude product is isolated as a solid by filtration, then the filtrate is diluted with water and extracted with four 300 ml. portions of chloroform. The combined extracts are washed with four 300 ml. portions of water and then with saturated sodium chloride solution and dried. Evaporation under vacuum provides a residue which is combined with the previously isolated crude solid product, 2-(4-fluorophenylthio)-5-nitroaniline. The solid is dissolved in 500 ml. of chloroform, then the solution is saturated with hydrogen chloride gas. The white precipitate which forms is separated by filtration, washed with chloroform and diethyl ether and dried to provide 2-(4-fluorophenylthio)-5-nitroaniline hydrochloride.