Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][C:25]([OH:24])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][CH2:27]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1C(=O)c2ccccc2C1C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.112 g) in methanol (5 mL) was treated with 4-hydroxy-4-phenylpiperidine (0.057 g) and the pH was adjusted to 6 by adding acetic acid. After treating with sodium cyanoborohydride (0.030 g), the reaction mixture was stirred at ambient temperature for 16 hours, diluted with a saturated solution of sodium bicarbonate, and extracted with dichloromethane. The organic layers were dried and evaporated to obtain 3-[1-(3,4-dichlorophenyl)-3-(4-hydroxy-4-phenylpiperidino)propyl]-2-methyl-2,3-dihydroiso-indol-1-one as a foam (0.104 g). This material was transformed into the hydrochloride salt as follows. The above product was dissolved in dry dichloromethane (2 mL) and treated with HCl in ether (2 mL). The resulting solution was diluted with anhydrous ether, stirred for 2 hours and the resulting precipitate was collected to afford the title compound (0.075 g); mp 160° C. (dec); MS: m/z=509(M+1); NMR: 1.79 (broad,2), 3.32 (s,3), 3.75 (broad,1), 4.88 (m,1), 5.44 (s,1), 6.80-7.95 (m,12). Analysis for C29H30Cl2N2O2.HCl. 0.5 H2O: Calculated: C, 62.76; H, 5.81; N, 5.13; Found: C, 62.79; H, 5.89; N, 4.89.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:25][CH3:26])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[H][H]>C1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:25][CH3:26])[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: [H][H]
Reactant: CCN(c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-])C1CCCCC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCN(c1ccc(C(=O)c2ccccc2)cc1N)C1CCCCC1

Procedure:
7.1 g. of 3-nitro-4-(N-ethyl-N-cyclohexylamino)-benzophenone are dissolved in a 1:1 mixture of benzene and ethyl acetate, and 0.7 g. of palladiumized carbon are added to the mixture. The mixture is hydrogenated at room temperature and 3 atm. hydrogen pressure until the uptake of the calculated amount of hydrogen (this requires about one hour). Thereafter the catalyst is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. 6.35 g. of crude product are obtained. After recrystallization from isopropanol, 5.8 g. of pure 3-amino-4-(N-ethyl-N-cyclohexylamino)-benzophenone, melting at 106.5°-107.5° C are obtained.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[OH-].[Na+].C1(C)C=CC=C(O[C:21](=[NH:25])[NH:22][C:23]#[N:24])C=1.C1C(O)=CC=CC=1C>C(O)(C)C>[C:21]([NH:22][C:23]([NH:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[NH:24])#[N:25]
Reactant: Cc1cccc(OC(=N)NC#N)c1
Reactant: NCCCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1cccc(O)c1
Product: N#CNC(=N)NCCCc1c[nH]cn1
Temperature: 25 °C

Procedure:
6.2 g. (0.031 mole) of 4-(3-aminopropyl)imidazole dihydrochloride is converted to the free base using NaOH. The free base is combined with 5.4 g. (0.031 mole) of O-m-tolyl-N-cyanoisourea in 100 ml. isopropanol. This mixture is refluxed for 3 hours. The mixture is then cooled to room temperature, filtered to remove insoluble material and the solvent is evaporated to obtain a cloudy oil of the product mixed with m-cresol.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[N:11]=[CH:12][O:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=S.[N:22]#[C:23][NH2:24].[Pb]>>[CH2:15]([C:14]1[O:13][CH:12]=[N:11][C:10]=1[CH2:9][NH:8][CH2:7][CH2:6][NH:5][C:3]([NH:24][C:23]#[N:22])=[N:2][CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CN
Reactant: CNC(=S)NCCNCc1ncoc1Cc1ccccc1
Agent: [Pb]
Product: CN=C(NC#N)NCCNCc1ncoc1Cc1ccccc1

Procedure:
Reacting ethylenediamine with 5-benzyl-4-chloromethyloxazole by the procedure of Example 34, then reacting the resulting N-(5-benzyl-4-oxazolylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and chromatographing gives N-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-((5-benzyl-4oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([CH:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([CH:22]3[CH2:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][CH2:27]3)[N:17]=2)[CH:4]=1
Reactant: CC1(C)CCC(n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)CC1
Yield: 85.8 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-117, 0.150 g, 0.348 mmol), KOH (0.039 g, 0.696 mol), water (2 mL) and THF (5.0 mL) to afford 0.100 g of the desired product.
Reaction SMILES: [CH:1]1([C:4]2(O)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH3:15][S:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2.FC(F)(F)C(O)=O.[Cl-].[NH4+]>ClCCl>[CH:1]1([C:4]2([C:23]3[C:22]4[C:26](=[C:18]([CH2:17][S:16][CH3:15])[CH:19]=[CH:20][CH:21]=4)[NH:25][CH:24]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: OC1(C2CC2)CCc2cc(F)ccc21
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
200 mg (0.78 mmol) of the compound from Example 76A with a purity of 75% and 152 mg (0.86 mmol) of the compound from Example 8A were introduced into 3.8 ml of dichloromethane at 0° C., 0.07 ml (0.94 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 175 mg (64% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([C:18]2[S:26][C:25]3[C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=4)=[N:23][CH:22]=[N:21][C:20]=3[CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([O:8][CH2:9][CH2:10][NH:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:24]2[C:25]3[S:26][C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:19][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: Nc1ccc(Nc2ncnc3cc(-c4ccccc4)sc23)cc1
Product: c1ccc(COCCNc2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc2)cc1

Procedure:
The title compound was prepared from benzyloxy-acetaldehyde (12 mg, 0.079 mmol) and N-(6-Phenyl-thieno[3,2-d]pyrimidin-4-yl)-benzene-1,4-diamine (150 mg, 0.471 mmol) by a procedure analogous to example 17. RP18-HPLC RT: 7.062 minutes; API MS: 452.58 (M+1) MP: 201-203° C.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1)[CH2:2][CH3:3].C(O)(=O)C.[Br:22]Br>O>[Br:22][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([NH2:16])[C:7]3[N:17]=[C:4]([CH2:1][CH2:2][CH3:3])[S:5][C:6]=3[C:15]=2[CH:14]=1
Reactant: BrBr
Reactant: CCCc1nc2c(N)nc3ccccc3c2s1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc2c(N)nc3ccc(Br)cc3c2s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 189.2 %

Procedure:
2-Propylthiazolo[4,5-c]quinolin-4-amine (1.0 g, 0.41 mmol) was combined with acetic acid (15 mL) and heated to 60° C. Bromine (0.10 mL, 1.94 mmol) was added dropwise and the reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was diluted with water and the resulting precipitate was isolated by filtration to provide 0.25 g of 8-bromo-2-propylthiazolo[4,5-c]quinolin-4-amine as a yellow solid, m.p. 177-180° C. Analysis: Calculated for C13H12BrN3S: % C, 48.46; % H, 3.75; % N, 13.04; Found: % C, 47.98; % H, 3.95; % N, 12.70.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][C:4]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].I([O-])(=O)(=O)=[O:26].[Na+].O>O.[Ru](=O)=O.C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([CH3:24])[CH2:3][C:4]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:7](=[O:26])[N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)CC1(CC(C)C)CCN(CCc2ccccc2)C1=O
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)CC1(CC(C)C)CC(=O)N(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Ruthenium(IV) oxide hydrate (27 mg, 0.20 mmol) is added to a mixture of ethyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (prepared similarly to that described in EXAMPLE 1, steps 1-3; 900 mg, 2.71 mmol), sodium periodate (2.71 g, 12.7 mmol), water (27 mL), and CCl4 (27 mL) at room temperature. After stirring overnight at room temperature, aqueous workup (CH2Cl2, MgSO4) and purification by column chromatography (20% EtOAc/hexane) gives 611 mg of the title compound (65%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:20]([OH:21])=[CH:19][C:17]([NH2:18])=[C:16]([F:22])[CH:15]=1>CC(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:18][C:17]3[CH:19]=[C:20]([OH:21])[C:14]([Cl:13])=[CH:15][C:16]=3[F:22])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CCCC(C)O
Product: Oc1cc(Nc2ccnc3cc(Cl)ccc23)c(F)cc1Cl
Yield: 79.8 %

Procedure:
Using an analogous procedure to that described for Example 15, 4,7-dichloroquinoline (198 mg, 1 mmol) was reacted with 4-chloro-2-fluoro-5-hydroxyaniline (194 mg, 1.2 mmol), (as described in EP 61741 A2), in 2-pentanol (5 ml) to give 7-chloro-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinoline (258 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=O)[C:3]=1[S:21]([CH3:23])=[O:22].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:25][OH:26])[C:3]=1[S:21]([CH3:23])=[O:22]
Reactant: NO
Reactant: CS(=O)c1c(C=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 61.1 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde (2.74 g), hydroxylamine hydrochloride (0.99 g) and pyridine (1.68 g) was stirred in methanol at 46° C. for 2.8 hours, evaporated, washed (water) and crystallized from ethanol to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.74 g) as a white solid m.p.219-221° C. (decomposition). Compound 1
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:21][C:10]1[C:11](=[O:14])[NH:12][CH:13]=[C:8]([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cc(C(c2ccccc2)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 23 h
Yield: 91.3 %

Procedure:
A mixture of 5-(diphenylmethyl)pyridin-2(1H)-one (0.3 g) and N-chlorosuccinimide(0.184 g) in DMF (3 mL) was stirred at ambient temperature for 23 hours. The reaction mixture was poured into saturated NaHCO3 aqueous solution and the resulting precipitates were collected by filtration and washed with water to afford 3-chloro-5-(diphenylmethyl)pyridin-2(1H)-one (0.31 g) as white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Oc1cccc2sccc12
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCOc1cccc2sccc12

Procedure:
3-Bromo-1-propanol (1.67 g) was added to a stirred solution of 4-hydroxybenzo[b]thiophene (1.50 g) and potassium carbonate (3.04 g) in 2-butanone (40 ml) under an atmosphere of nitrogen and the mixture was heated under reflux for 3 hours. The mixture was filtered and the filtrate evaporated to dryness. The solid residue was recrystallised from ethanol to give 4-(3-hydroxypropyloxy)benzo[b]thiophene of m.p. 82° C. A solution of N-chloroacetylpyrrolidine (1.47 g) in tetrahydrofuran (THF, 10 ml) was added in one portion to a stirred solution of 4-(3-hydroxypropyloxy)benzo[b]thiophene (1.75 g) and sodium hydride (60% suspension, 0.40 g) in tetrahydrofuran under an atmosphere of nitrogen and stirring was continued for 1 hour at room temperature. The solution was filtered and the filtrate evaporated to afford an oil, which was purified by flash chromatography (silica, ethylacetate:petroleum, 1:1 v/v) to yield the pyrrolidine amide of 3-(4-benzothiophenoxy)propyloxy acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](Br)([Br:18])[C@@H:14]2[C:20]2[CH:25]=[CH:24][C:23]([CH:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:8][CH:9]=1)=[O:4].C(N=C(N(C)C)N(C)C)(C)(C)C.Cl>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([Br:18])=[C:14]2[C:20]2[CH:21]=[CH:22][C:23]([CH:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(Br)Br)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: ClCCCl
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(Br)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 72 h
Yield: 15 %

Procedure:
A solution of dibromide 3 (52 mg, 0.074 mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 0.8 mL) in 1,2-dichloroethane (2 mL) was stirred at room temperature. After 3 days, 1 M HCl was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (0%→20% ethyl acetate/hexanes) gave the title compound contaminated with 15% of the alkene regioisomer 5b as an inseparable mixture (45 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15]OC1C=CC=C(C)C=1C.CC1C(C)=CC=CC=1OCCCC(O)=O.[CH3:41][O:42][C:43](C1(C(O)=O)CC1)=[O:44]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([C:13]1([C:43]([O:42][CH3:41])=[O:44])[CH2:14][CH2:15]1)=[O:25]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: Cc1cccc(OCCCC(=O)O)c1C
Product: COC(=O)C1(C(=O)N2CCCc3c(Br)cccc32)CC1

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that 4-(2,3-dimethylphenoxy)butanoic acid was replaced with 1-(methoxycarbonyl)cyclopropanecarboxylic acid. LCMS, [M+H]+=338.0.
Reaction SMILES: C([O-])(O)=O.[Na+].[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[NH:16][S:15](=[O:18])(=[O:17])[CH2:14][C:13]=2[CH:19]=1)([O-:8])=[O:7].Br[CH2:21][CH2:22][F:23]>O>[F:23][CH2:22][CH2:21][N:16]1[C:12]2[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:19][C:13]=2[CH2:14][S:15]1(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)CS(=O)(=O)N2
Reactant: FCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CS(=O)(=O)N2CCF
Temperature: 80 °C
Yield: 66.9 %

Procedure:
NaHCO3 (0.93 g, 11.0 mmol) is dissolved in H2O (15 mL) and 5-Nitro-1,3-dihydro-2H-2,1-benzisothiazole-2,2-dione (1) (1.90 g, 8.9 mmol) is added with stirring. The mixture is heated to 80° C. for 0.5 hrs and a yellow solid formed. The mixture is cooled to 0° C. and filtered. The solid is washed with cold H2O (15 mL) then with cold EtOH (25 mL). The yellow solid thus obtained is dried under high vacuum then dissolved in dry DMF (15 mL). 1-Bromo-2-fluoroethane (1.52 mL, 20.0 mmol) is added and the solution heated to 100° C. for 4 hrs. The solution is cooled to room temperature then poured into ice water (50 mL). The solid is collected by filtration and gave crystals (1.55 g, 67%) after recrystallization from EtOH. Mp 142-4° C. HRMS (FAB) calcd for C9H9FN2O4S +NA1 283.0165, found 283.0166.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(O)(=O)C.C(NC(=O)[O-])C.[CH:19]1([CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]3[CH:28]([CH3:36])[CH:29]4[CH2:33][NH:32][CH2:31][CH:30]4[C:34]=3[CH:35]=2)[CH2:21][CH2:20]1>ClCCCl>[CH:19]1([CH2:22][O:23][C:24]2[C:25]([Cl:8])=[CH:26][C:27]3[CH:28]([CH3:36])[CH:29]4[CH2:33][NH:32][CH2:31][CH:30]4[C:34]=3[CH:35]=2)[CH2:20][CH2:21]1
Reactant: CC1c2ccc(OCC3CC3)cc2C2CNCC12
Reactant: O=C1CCC(=O)N1Cl
Agent: CCNC(=O)[O-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1c2cc(Cl)c(OCC3CC3)cc2C2CNCC12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
NCS (38 mg, 0.28 mmol) and acetic acid (1 mL) were added to a solution of N-ethylcarbamate-5-cyclopropylmethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (89 mg, 0.28 mmol) in DCE (2 mL), and the reaction solution was stirred for 3 hours at 70° C. The reaction was quenched with H2O and the solution filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C19H24ClNO3+H: 350, observed: 350.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][CH3:22])[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:24][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[N:10]([CH2:21][CH3:22])[C:9](=[O:23])[CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2ccc(OC)cc21
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2cc(Br)c(OC)cc21
Yield: 77.1 %

Procedure:
A solution of 3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3.38 g, 10.58 mmol) and N-bromosuccinimide (2.072 g, 11.64 mmol) in acetic acid (2.5 mL) and chloroform (25 mL) was heated at reflux for 2 hrs. The reaction mixture was diluted with chloroform (25 mL), washed with saturated aqueous solution of NaHCO3 and water, dried over Na2SO4, filtered and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel column eluted with EtOAc/hexane (3:7) provided the desired compound (3.25 g, 77%) as white powder.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][C:11]1([C@@H:14]2[O:22][CH2:21][C:17]3=[N:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:13][CH2:12]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@:17]12[CH2:21][O:22][C@@H:14]([C:11]3([CH3:10])[CH2:12][CH2:13]3)[CH2:15][C@H:16]1[CH2:20][O:19][NH:18]2
Reactant: Fc1ccc(I)c(F)c1
Reactant: CC1([C@H]2C[C@H]3CON=C3CO2)CC1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1([C@H]2C[C@H]3CON[C@@]3(c3ccc(F)cc3F)CO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (7.86 g, 25.9 mmol) was added drop-wise to a solution of rel-(3aR,5R)-5-(1-methylcyclopropyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C56) (4.255 g, 23.5 mmol) in toluene (500 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 6.22 g, 25.9 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 9.9 mL, 24.8 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (400 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 3.2 g, 10.8 mmol, 46%. LCMS m/z 296 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J=8.3 Hz, 1H), 6.88 (dt, J=8.4, 2.4 Hz, 1H), 6.78 (ddd, J=11.6, 8.8, 2.4 Hz, 1H), 6.28 (br s, 1H), 4.04 (dd, J=12.4, 1.6 Hz, 1H), 3.82 (d, J=12.8 Hz, 1H), 3.72 (d, J=6.8 Hz, 1H), 3.53 (dd, J=6.8, 4.8 Hz, 1H), 3.01-3.06 (m, 1H), 2.95 (d, J=12.0 Hz, 1H), 1.83 (dd, J=13.2, 6.0 Hz, 1H), 1.62 (q, J=12.4 Hz, 1H), 1.09 (s, 3H), 0.52-0.56 (m, 1H), 0.43-0.48 (m, 1H), 0.36-0.41 (m, 1H), 0.28-0.33 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.C([N:16](CC)CC)C.[OH-].[NH4+].O>O1CCCC1>[NH2:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: CCN(CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=S)c1cnc(C)nc1N
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (25.4 g, 106 mmol, Aldrich Chemical Co., Milwaukee, Wis., USA) in 300 mL of tetrahydrofuran was treated with 50 mL of triethylamine and 40 mL of aqueous ammonium hydroxide. After stirring for 4 hours, 300 mL of water was added and the phases were separated. The organic layer was washed with 300 mL of brine, concentrated in vacuo, dissolved in methylene chloride, dried over sodium sulfate, filtered and concentrated in vacuo to give 16.5 g (95%) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid.