Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:8]1([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:7].N.[Br:32]Br>ClCCl>[CH3:27][O-:28].[CH2:6]([C:8]1([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][C:22]([Br:32])=[CH:21][CH:20]=4)[CH3:7]
Reactant: CCC1(CCC(=O)OC)CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Reactant: BrBr
Agent: N
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CCC1(CCC(=O)OC)CCC[N+]2=C1c1[nH]c3ccc(Br)cc3c1CC2
Product: C[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4.39 g. (10 mmoles) of 1-ethyl-1-(2'-methoxycarbonylethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-quinolizin-5-ium perchlorate are shaken with a mixture of 5 ml. of 10% aqueous ammonia and 50 ml. of dichloromethane. The phases are separated, the organic phase is dried over 10 g. of solid anhydrous sodium sulfate, filtered, the filtrate is evaporated to a final volume of about 40 ml., and 0.1 g. of dry ferric chloride are added to this concentrate. 2.08 g. (0.67 ml., 13 mmoles) of elemental bromine are added dropwise, under vigorous stirring, to this mixture at 25° C. The addition takes place in 5 minutes. The reaction mixture is stirred at room temperature for 2 hours, thereafter it is rendered alkaline with 10 ml. of 10% aqueous ammonia, and the precipitated ferric hydroxide is filtered off. The organic phase of the filtrate is separated, dried over 10 g. of solid anhydrous sodium sulfate, filtered, and the filtrate is evaporated. The oily residue is admixed with 10 ml. of methanol, whereupon the product separates in crystalline form containing lattice-bound methanol. In this way 3.81 g. (85%) of 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-quinolizin-5-ium methoxide are obtained; m.p.: 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](O)=[O:15])=[CH:8][CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].O.C(Cl)[Cl:26]>C1(C)C=CC=CC=1>[ClH:26].[OH:15][CH2:14][C:13]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:22]([CH3:23])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(C(=O)O)c1CNc1cccn2c(C)c(C)nc12
Reactant: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(CO)c1CNc1cccn2c(C)c(C)nc12
Product: Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 12 %

Procedure:
To an icecooled mixture of 2-(((2,3-dimethylimidazo[1,2-a]pyridin-8-yl)amino)methyl)-3-methylbenzoic acid (0.18 g, 0.59,mmol) in toluene (30 ml) was added dropwise Red-A1 (5 ml) in toluene (7 ml) and was stirred at room temperature for 20 h. The mixture was cooled with ice and water (10 ml) and methylene chloride were added. After filtration the filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (100:5) as eluent. The product was solved in methylene chloride/ether and treated with HCl/diethyl ether to give 0.024 g (12%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:16])=[C:5]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[O:6][CH2:7][C:8]([OH:10])=[O:9])#[N:2].[OH-:17].[Na+]>>[C:1]([C:3]1[C:4]([I:16])=[C:5]([C:11]([I:15])=[CH:12][C:13]=1[I:14])[O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:17])[NH2:2]
Reactant: N#Cc1c(I)cc(I)c(OCC(=O)O)c1I
Reactant: [OH-]
Agent: [Na+]
Product: NC(=O)c1c(I)cc(I)c(OCC(=O)O)c1I

Procedure:
27.3 g (49 mmol) of 3-cyano-2,4,6-triiodophenoxyacetic acid is stirred in 100 of 2N sodium hydroxide solution for 3 hours at 50° C. The resultant alkaline solution is filtered over active carbon for purifying and decolorizing and then brought to pH 2 by adding 2N hydrochloric acid. After several hours of stirring in an ice bath, the yield is 23.9 g (85% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp 211°-213° C. (decomposition).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([S:18][C:19]#[N:20])[CH:15]=[CH:14][C:12]=2[N:13]=1>N1C=CC=CC=1>[C:5]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([S:18][C:19]#[N:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)(=[O:7])[CH3:6]
Reactant: N#CSc1ccc2nc(N)sc2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(SC#N)cc2s1
Reaction time: 0.08 h

Procedure:
5 cm3 of acetic anhydride are added dropwise to 7 cm3 of pyridine at 20° C. After 5 min, 1 g of 2-amino-6-thiocyanatobenzothiazole (commercial) is added. The yellow suspension is stirred for 4 h and then concentrated to dryness under vacuum. The residue is made into a paste in ethyl ether. The insoluble material is isolated by filtration, to give 1.1 g of 2-(acetylamino)-1,3-benzothiazol-6-ylthiocyanate in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[CH3:35]CN(C(C)C)C(C)C.CI>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[N:18]([CH3:35])[CH:19]=[C:20]([CH2:24][C:25]4[CH:30]=[N:29][CH:28]=[N:27][CH:26]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: O=c1nc(CCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC(Cl)Cl
Product: Cn1cc(Cc2cncnc2)c(=O)nc1CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
To the solution of 2-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (200 mg, 0.411 mmol) in dichloroethane (5 ml) was added DIPEA (0.143 ml, 0.822 mmol). It was stirred at rt for 30 min, mixed with MeI (0.031 ml, 0.493 mmol) dropwise, then stirred at r.t. overnight. Purification via MDAP then afforded the title compound (16 mg, 7.8%). LCMS: rt=3.04 min, [M+H+]=501
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH3:31].C1CCCCC=1.C(O)C>[OH-].[OH-].[Pd+2].O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:21][CH:22]=2)=[CH:11][C:10]=1[CH3:31]
Reactant: Cc1cc(/C=C/c2ccc(OCCCCCCO)cc2)ccc1OCCCCCCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1cc(CCc2ccc(OCCCCCCO)cc2)ccc1OCCCCCCO
Yield: 84 %

Procedure:
A mixture of 2.1 g (5.0 mmol) of (E)-4,4′-di-(6-hydroxyhexyloxy)-3-methylstilbene (3), synthesized in accordance with the method described in the European patent application having application number 01204081.2 filed by Applicant (Applicant's reference PHNL010757), 0.25 g of Pd(OH)2 on carbon, 35 ml of cyclohexene and 50 ml of ethanol is refluxed for one night. The hot solution is passed through Celite and added dropwise to 400 ml of water. The precipitated product is washed with water. 1.8 g of the product (86%) was obtained after drying.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([F:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([C:33](=[O:34])[C:32]2[CH:31]=[C:30]([F:29])[CH:38]=[C:37]([F:39])[CH:36]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3,5-difluorobenzoyl chloride gave the title compound.
Reaction SMILES: [CH:1]1([CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](CC(O)=O)=[CH:11][CH:10]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:19].[Na+].O.[CH2:22]([OH:24])[CH3:23]>>[C:22]([O:19][C:12]1[CH:11]=[CH:10][C:9]([NH:8][CH:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH3:7])=[CH:14][CH:13]=1)(=[O:24])[CH3:23]
Reactant: CCO
Reactant: CC(Nc1ccc(CC(=O)O)cc1)C1CCCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1ccc(NC(C)C2CCCC2)cc1

Procedure:
A mixture of 3.62 g. of 4-(1-cyclopentylethylamino)phenylacetic acid and 25 ml. of ethanol water (9:1) containing 0.400 g. of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the residue washed with 10 ml. of ethanol-water (9:1) and dried in vacuo for 24 hours to yield 4-(1-cyclopentylethylamino)phenyl acetate as a white solid.
Reaction SMILES: CCN(CC)CC.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:31][C:28]([CH3:30])([CH3:29])[C:25]([CH3:27])([CH3:26])[O:24]2)=[CH:19][CH:18]=1.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:29][C:28]1([CH3:30])[C:25]([CH3:26])([CH3:27])[O:24][B:23]([C:20]2[CH:21]=[CH:22][C:17]([N:16]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]3=[O:14])=[CH:18][CH:19]=2)[O:31]1
Reactant: O=C(Cl)CCCCBr
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(N3CCCCC3=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 36.1 %

Procedure:
Et3N (239 μL, 1.71 mmol) and 5-bromovaleroyl chloride (166 μL, 1.26 mmol) were added to a solution of 4-aminophenylboronic acid pinacol ester (250 mg, 1.14 mmol) in DCM (5 mL) at 0° C. After stirring the mixture for 18.5 hours at room temperature, the mixture was concentrated. The residue was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated. The residue was diluted with DMF (5 mL) and NaH (55% in liquid paraffin, 62.2 mg, 1.43 mmol) at 0° C. After stirring the mixture for 21 hours at room temperature, the mixture was concentrated. The residue was diluted with 10% aqueous citric acid and extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (EtOAc/hexane=1:1) to afford desired product (124 mg, 36.1%) as white solid. 1HNMR (CDCl3) 400 MHz δ: 7.86-7.81 (m, 2H), 7.30-7.24 (m, 2H), 3.70-3.60 (m, 2H), 2.61-2.51 (m, 2H), 2.00-1.87 (m, 4H), 1.33 (s, 12H).
Reaction SMILES: OC[C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([CH3:12])=[CH:5][N:4]=1.[CH:13]([Cl:16])(Cl)[Cl:14]>>[ClH:14].[Cl:16][CH2:13][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([CH3:12])=[CH:5][N:4]=1
Reactant: ClC(Cl)Cl
Reactant: COc1c(C)cnc(CO)c1C
Product: COc1c(C)cnc(CCl)c1C
Product: Cl
Temperature: 25 °C
Yield: 69 %

Procedure:
To a solution of crude 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine (23.41 g, 0.41 mol) in CHCl3 (70 ml) was added SO2Cl2 (30 ml, 0.42 mol) at ice bath temperature. The reaction mixture was refluxed for 2 h and cooled to rt. Evaporation of the solvent in vacuo gave a dark brown solid. Recrystallization from isopropanol-ether gave 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (14) (21.6 g, 69%) as a white solid; mp 135-136° C. For previous syntheses see references cited in Brandstrom et al., Acta Chemica Scandinavia 43: 536-548, 1989 and GB 2134523.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[Cl:15].Cl[C:17](OC(Cl)(Cl)Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:5]1[C:6]2[C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[O:9][C:10]=2[C:2]([N:1]=[C:17]=[O:18])=[C:3]([Cl:15])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)Oc2c(N)c(Cl)cc(Cl)c2C1=O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2c(N=C=O)c(Cl)cc(Cl)c2C1=O

Procedure:
To a solution of 4.00 g (0.0163 mole) of 7-amino-4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-one in 80 mL of toluene at ambient temperature was added 3.22 g (0.0163 mole) of trichloromethyl chloroformate. This mixture was stirred for fifteen minutes before being heated at reflux for three hours. The solvent was evaporated under reduced pressure, leaving 4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl isocyanate as a pale yellow oil. Upon standing, this oil solidified. The IR spectrum was consistent with an isocyanate. Step E Synthesis of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl)-6-trifluoromethyluracil
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[CH3:33][NH:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][CH:35]([NH:34][CH3:33])[CH2:36]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)ccc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)c(N)n4)c3c2Br)C1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To 250 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-5-fluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 10 minutes. After adding 0.5 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 66 mg of the title compound as a colorless powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][CH2:16][CH2:17][O:18][CH3:19].[I-].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COCCCBr
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCn1ccc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of methyl 1H-indole-6-carboxylate (5.0 g) in N,N-dimethylformamide (40 mL) was added dropwise a solution of 1-bromo-3-methoxypropane (5.24 g) in N,N-dimethylformamide (10 mL) under ice-cooling, and then thereto was added potassium iodide (948 mg), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was sequentially added ethyl acetate and water under ice-cooling, and the organic layer was separated. The organic layer was washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1→4/1) to give methyl 1-(3-methoxypropyl)-1H-indole-6-carboxylate [REx(6-1)] (5.8 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:11][CH2:12][CH2:13][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCCl
Temperature: 115 °C
Reaction time: 1 h

Procedure:
2-Nitro-phenol (168.7 g) and toluene-4-sulfonic acid 2-chloroethyl ester (100 g) were dissolved in 500 ml DMF and were stirred for 1 h at 110-120° C. after careful addition of 199 g potassium carbonate. The reaction mixture was poured in a mixture of crushed ice and water (8 L) which was vigorously stirred. The residue was filtered off, washed several times with water and dried. Yield: 100-120 g.
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[CH:13][N+:14]([O-:16])=[O:15])(=[O:6])=[O:5].CCOCC>C(Cl)Cl>[CH3:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:13]([Br:1])[N+:14]([O-:16])=[O:15])(=[O:5])=[O:6]
Reactant: BrBr
Reactant: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCSC1=C(Br)[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 1.6 g of bromine in 10 ml of methylene chloride was added drop-by-drop over a period of 10 minutes to a solution of 2.38 g of (1A) in 50 ml of methylene chloride at 0° C. and under a nitrogen blanket. The resulting mixture was stirred for a further 10 minutes, charcoaled, and stripped of solvent. The residue was dissolved in a minimum amount of methylene chloride, then ether was added to the solution, resulting in a gum. The gum was dissolved in methylene chloride, the solution was charged onto a flash chromatograph column (silica gel) and the product was eluted with methylene chloride, to give (1) on workup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH2:8]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1ccc(C=CCCl)cc1OC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1OC
Yield: 7.7 %

Procedure:
Prepared from 3,4-dimethoxy-cinnamyl chloride (prepared at -5° C. for 10 minutes) and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 7.7% of theory, Melting point: 122°-126° C. (ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C:15]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(C(OCC)=O)[C:16]([O:18]CC)=[O:17])=[CH:12][N:11]=[C:10]1[S:33][CH2:34][CH2:35][CH3:36].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH:15]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:16]([OH:18])=[O:17])=[CH:12][N:11]=[C:10]1[S:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCSc1ncc(CC(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCSc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Yield: 87.4 %

Procedure:
A mixture of diethyl [1-{(2-chlorophenyl)methyl}-2- propylthio-1H-imidazol-5-yl]methyl-2-benzyl-malonate (0.72 gl 1.36 mmol), potassium hydroxide (0.83 g, 14.7 mmol), water (15 mL)-and ethanol (25 mL) was refluxed for 4 hours. The ethanol was evaporated, the residual aqueous layer was extracted with diethyl ether, and the basic solution was adjusted to pH 3.75 with concentrated hydrochloric acid. The precipitated product was extracted into methylene chloride, dried, and concentrated. This crude product was flash chromatographed on silica gel with 10% methanol in methylene chloride to give 0.51 g (86%) of 3-[1-{(2chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp 123°-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18]C)=[O:17])[NH:7][C:6]=2[CH:22]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:3]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([OH:18])=[O:17])[NH:7][C:6]=2[CH:22]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(C#Cc4ccccc4F)c(Cl)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Oc2nc3cc(C#Cc4ccccc4F)c(Cl)cc3[nH]2)cc1C(=O)O

Procedure:
A solution of methyl 5-({6-chloro-5-[(2-fluorophenyl)-ethynyl]-1H-benzimidazol-2-yl}oxy)-2-methylbenzoate (910 mg, 2.1 mmol) and 4.2 mL 5 M aqueous NaOH in 15 mL MeOH and 15 mL water was heated at 70° C. for 30 min. Volatiles were removed. The residue was dissolved in water (30 mL), and acidified with 2 N aqueous HCl, the precipitated solid was filtered (rinsing with water) and dried to afford the desired product as a white solid. LC/MS: calculated for C23H14ClFN2O3 420, observed mile 421 (M+H)+ (2.1/4 min). 1H NMR (500 MHz, CD3OD): δ 7.88-7.16 (9H, m), 2.61 (3H, s).
Reaction SMILES: [F:1][C:2]1[C:14]2[C:13](O)([C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=3[F:25])[C:12]3[C:7](=[C:8]([F:30])[C:9]([F:29])=[C:10]([F:28])[C:11]=3[F:27])[C:6]=2[C:5]([F:31])=[C:4]([F:32])[C:3]=1[F:33].P(Br)(Br)Br>>[F:1][C:2]1[C:14]2[CH:13]([C:15]3[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=3[F:21])[C:12]3[C:7](=[C:8]([F:30])[C:9]([F:29])=[C:10]([F:28])[C:11]=3[F:27])[C:6]=2[C:5]([F:31])=[C:4]([F:32])[C:3]=1[F:33]
Reactant: OC1(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2-c2c(F)c(F)c(F)c(F)c21
Agent: BrP(Br)Br
Product: Fc1c(F)c(F)c(C2c3c(F)c(F)c(F)c(F)c3-c3c(F)c(F)c(F)c(F)c32)c(F)c1F
Temperature: 110 °C
Yield: 84.2 %

Procedure:
4.5 g (0.009 moles) of 1,2,3,4,5,6,7,8-octafluoro-9-hydroxy-9-(pentafluorophenyl)fluorene (XII), prepared as described in the preceeding example 7, are added to 25 ml (0.26 moles) of PBr3 and heated to 110° C. for 30 minutes in an inert atmosphere. The reaction mass is hydrolyzed in ice, extracted with ethyl ether, the extract is washed with an aqueous solution (10%) of NaHCO3, dried on sodium sulfate, filtered and dried. The residue is purified by chromatography on a silica gel column (eluant: petroleum ether/methylene chloride, 98/2), obtaining, after evaporation of the pure fractions, 3,61 g of white crystalline product (yield 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][C@@H:19]3[CH2:18][O:17][C:16]=2[C:15]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][C@@H:19]3[CH2:18][O:17][C:16]=2[C:15]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)c1c(N)ccc2c1OC[C@H]1CCN21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCN21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.091 g) was added to a solution of tert-butyl (R)-6-amino-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (Intermediate 44, 0.092 g) in pyridine (2 mL) and DCM (2 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between DCM and 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give tert-butyl (R)-6-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta-[a]naphthalene-5-carboxylate (0.062 g).