Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:44][C:45]([F:52])([F:51])[CH2:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:19][O:18][C:17]1[CH:36]=[CH:37][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:47]([CH2:46][C:45]([F:52])([F:51])[F:44])(=[O:49])=[O:48])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(CC(F)(F)F)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and pyridine (0.06 g, 0.75 mmole) in methylene chloride (20 ml) at 0° was added, dropwise, a solution of 2,2,2-trifluoroethanesulphonyl chloride (0.095 g, 0.52 mmole) in methylene chloride (1 ml) and the resulting mixture was stirred for 0.5 hour. The reaction was quenched by the addition of aqueous citric acid, the resulting organic phase separated, washed with water and dried over magnesium sulphate. After concentration under reduced pressure the residue was purified by flash chromatography on silica gel eluting with ethyl acetate (80):hexane (20) to yield, after collection and evaporation of appropriate fractions, the desired product as a foam, m.p. 74°-75° (0.159 g, 62%).
Reaction SMILES: [CH:1]([CH:4]([C:7]1[CH:15]=[CH:14][C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=1)[C:5]#N)([CH3:3])[CH3:2].[OH-:16].[K+].C(O)C[OH:20]>O>[CH:1]([CH:4]([C:7]1[CH:15]=[CH:14][C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=1)[C:5]([OH:20])=[O:16])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)C(C#N)c1ccc2ccoc2c1
Reactant: OCCO
Agent: [K+]
Solvent: O
Product: CC(C)C(C(=O)O)c1ccc2ccoc2c1
Temperature: 140 °C
Yield: 50.8 %

Procedure:
A mixture of α-isopropylbenzofuran-6-acetonitrile (1.62 g, 0.008 mol), potassium hydroxide (2.29 g, 0.039 mol), ethane-1,2-diol (28 cm3) and water (2.3 cm3) was refluxed at 140° C. for 18 hr. The cooled mixture was poured into water and extracted with diethyl ether. The aqueous solution was acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ether extract was washed with water, dried (Na2SO4), filtered and the solvent was removed to give α-isopropylbenzofuran-6-acetic acid (0.90 g, 0.0041 mol, 50.8%). Recrystallised from petroleum ether (b.p. 60°-80° C.) m.p. 99°-100° C. (Found: C, 71.52; H, 6.65; C13H14O3 requires C, 71.54; H, 6.47%), t.l.c./silica/ethyl acetate RF 0.40.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2ccccc2)cc1
Yield: 27.4 %

Procedure:
A solution of 4-(phenylamino)benzoic acid (0.048 g, 0.225 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.052 g; 0.225 mmol), HATU (0.094 g; 0.247 mmol) and N,N-diisopropylethylamine (0.097 mL; 0.563 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.024 g (27%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH:20]=[CH2:21].[CH3:22][C:23]([CH3:25])=[O:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH2:19][CH:20]=[CH2:21])=[C:6]([CH:7]([OH:8])[CH2:22][C:23](=[O:24])[CH3:25])[CH:9]=1
Reactant: C=CCCBr
Reactant: CC(C)=O
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCOc1ccc(Br)cc1C(O)CC(C)=O

Procedure:
To 300 ml of acetone there are added 10 g of 5-bromo-2-hydroxybenzaldehyde (49.7 mmol), 13.7 g of potassium carbonate (99.5 mmol) and 10.1 ml of 4-bromobut-1-ene (99.5 mmol); the reaction mixture is then heated at reflux for 36 hours before being cooled, filtered and evaporated to dryness to yield 4-[5-bromo-2-(but-3-en-1-yloxy)phenyl]-4-hydroxybutan-2-one in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH3:24]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([CH3:24])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Reactant: CB(O)O
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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (0.49 g, 1.5 mmol), methylboronic acid (1.8 g, 29 mmol), and tetrakis(triphenylphosphine)palladium (0.086 g, 0.074 mmol) in toluene (30 mL) is stirred for 10 minutes under N2 atmosphere. A solution of sodium carbonate (6.3 g, 59 mmol) in water (20 mL) is added and the mixture is heated at 100° C. for 48 hours. After cooling to room temperature, the reaction mixture is diluted with water (20 mL) and extracted with EtOAc. The combined extracts are washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with hexane/EtOAc 20/1) to give 6-(2,6-diethyl-phenyl)-2,4-dimethyl-nicitinic acid ethyl ester as a colorless oil: 1H NMR (CDCl3) 7.27 (dd, 1H), 7.12 (d, 2H), 6.96 (s, 1H), 4.47 (q, 2H), 2.60 (s, 3H), 2.38 (s, 3H), 2.36-2.28 (m, 4H), 1.45 (t, 3H), 1.05 (t, 6H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([O:13]CC(C)=C)[CH:9]=[CH:8][C:7]=2[CH3:18])[CH3:2]>C(Cl)(Cl)Cl.CO.CCCCCC>[CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[C:9]([CH2:12][C:3]([CH3:4])=[CH2:1])=[CH:8][C:7]=2[CH3:18])[CH3:2]
Reactant: C=C(C)COc1ccc(C)c2[nH]c(=O)c(CC)cc12
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCCCCC
Product: C=C(C)Cc1cc(C)c2[nH]c(=O)c(CC)cc2c1O
Yield: 150.8 %

Procedure:
Using 3-ethyl-5-(2-methyl-2-propenyl)oxy-8-methylcarbostyril (0.94 g, 3.66 mmol), the procedure of Reference Example 32 was followed (reaction, post-treatment, and recrystallization from chloroform-methanol-n-hexane) to obtain 710 mg of the title compound as pale yellow crystals (75.5%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[S:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[S:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)c(F)c2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5nc6ccccc6s5)c(F)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
Trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzothiazol-2-amine was prepared from trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) and N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine (0.105 g, 0.283 mmol) in a manner similar to that used for the cis-isomer. The compound was formed as a white powder (0.052 g, 41%):
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[OH-].[K+].ClCCl>C(O)CCC>[OH:1][C:2]1[C:3]([C:13]([O:15][CH2:3][CH2:2][CH2:11][CH3:6])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc2ccc(C)nc2c1O
Temperature: 20 °C
Yield: 143.8 %

Procedure:
A mixture of 8-hydroxy-7-quinaldinecarboxylic acid 1 (12 g, 59 mmol) and polyphosphoric acid (30 g) in 60 ml of n-butanol is heated at 100° C. for 72 hours during which additional portions of 30 g of polyphosphoric acid and 30 ml of n-butanol are regularly added every 12 hours. After cooling to 20° C., the reaction mixture is brought to pH 4 with a 6 N potassium hydroxide solution, and then 200 ml of dichloromethane are added. The phases are separated, and the aqueous phase extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on a silica column, eluting with a 1/1 cyclohexane/ethyl acetate mixture so as to give 11 g (72%) of n-butyl 8-hydroxy-2-methylquinoline-7-carboxylate in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1([C:10]2[CH:29]=[CH:28][C:13]([CH2:14][N:15]3[C:19]4=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]4[N:17]=[C:16]3[S:25][CH2:26][CH3:27])=[CH:12][CH:11]=2)[CH2:6][C:5]([C:7]#[N:8])=[CH:4][N:3]1[CH3:9].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1([C:10]2[CH:29]=[CH:28][C:13]([CH2:14][N:15]3[C:19]4=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]4[N:17]=[C:16]3[S:25][CH2:26][CH3:27])=[CH:12][CH:11]=2)[CH2:6][C:5]([C:7]2[NH:36][N:35]=[N:34][N:8]=2)=[CH:4][N:3]1[CH3:9]
Reactant: CCSc1nc2c(C)ccnc2n1Cc1ccc(C2(Br)CC(C#N)=CN2C)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCSc1nc2c(C)ccnc2n1Cc1ccc(C2(Br)CC(c3nnn[nH]3)=CN2C)cc1
Reaction time: 36 h
Yield: 48.7 %

Procedure:
To a stirred solution of 3-[4-(2-bromo-4-cyano-1-methyl-2-pyrrolyl)benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (1.30 g) in xylene (15 ml) was added trimethyltin azide (1.72 g) at 125° C., stirred at the same temperature for 36 hours under nitrogen atmosphere, and the mixture was evaporated in vacuo. The residue was diluted with methanol and conc. hydrochloric acid (1 ml) was added therein. The mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo. The residue was diluted with methanol and adjusted to pH4 with aqueous 1N sodium hydroxide. The organic layer was separated, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (elution by dichloromethane/methanol=15/1) and by preparative thin layer chromatography (elution by dichloromethane/methanol=8/1) to yield 3-[4-[2-bromo-1-methyl-4-(1H-tetrazol-5yl)-2-pyrrolyl]benzyl-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (691 mg) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([N+:20]([O-])=O)=[C:16]([CH:19]=2)[C:17]#[N:18])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:24]N>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:19]=[C:16]3[C:15](=[CH:14][CH:13]=2)[NH:20][N:18]=[C:17]3[NH2:24])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1cc(S(=O)(=O)c2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12
Yield: 73 %

Procedure:
5-(3,5-Difluoro-benzenesulfonyl)-2-nitro-benzonitrile (3.5 g, 10.8 mmol) was heated in anhydrous ethanol (175 mL) until completely dissolved. The solution was then treated with hydrazine hydrate (0.58 mL, 1.1 mol eq.) and refluxed for three hours. The reaction mixture was evaporated to dryness; the residue was dissolved in acetone, adsorbed onto flash chromatography-grade silica gel by rotoevaporation of the solvent. The silica was loaded onto a flash chromatography column conditioned with 10:1 dichloromethane/acetone. The column was then eluted with dichloromethane/acetone (gradient: from 10:1 to 2:1) followed by a final washing with dichloromethane/acetone/methanol. The pure fractions were collected and evaporated to afford the title compound as a whitish crystalline powder (2.44 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH3:27][N:28]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N+:38]([O-:40])=[O:39])(=[O:31])=[O:30]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:44]2[CH2:43][CH2:42][CH:41]([N:28]([CH3:27])[S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N+:38]([O-:40])=[O:39])(=[O:31])=[O:30])[CH2:46][CH2:45]2)=[O:16])=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CN(C1CCNCC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Product: CN(C1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
Prepared according to EXAMPLE 231 from 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)-propionic acid (EXAMPLE 230) and N-methyl-2-nitro-N-piperidin-4-yl-benzenesulfonamide hydrochloride (Preparation 75). m/z (ES+)=643.36 [M+H]+.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([N:10]([CH2:15][C:16]#C)[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].[CH3:18][N:19]1[C:27]2[N:26]=[CH:25][N:24]([CH2:28][CH2:29][CH3:30])[C:23]=2[C:22](=[O:31])[N:21]([CH2:32][CH2:33][C:34](=[O:36])[CH3:35])[C:20]1=[O:37].Cl>CCCCCC.O1CCCC1>[CH2:11]([N:10]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:15][C:16]#[C:35][C:34]([OH:36])([CH3:1])[CH2:33][CH2:32][N:21]1[C:22](=[O:31])[C:23]2[N:24]([CH2:28][CH2:29][CH3:30])[CH:25]=[N:26][C:27]=2[N:19]([CH3:18])[C:20]1=[O:37])[CH2:12][CH2:13][CH3:14]
Reactant: C#CCN(CCCC)CCCC
Reactant: [Li]CCCC
Reactant: CCCn1cnc2c1c(=O)n(CCC(C)=O)c(=O)n2C
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCN(CC#CC(C)(O)CCn1c(=O)c2c(ncn2CCC)n(C)c1=O)CCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.73 ml (10.77 mmol) of a 15% strength butyllithium solution in n-hexane were slowly added dropwise to a solution of 2.09 ml (10.77 mmol) of N,N-dibutyl-2-propynylamine in 20 ml of tetrahydrofuran at -65° C. The mixture was stirred at -60° C. to -65° C. for one hour and warmed to room temperature, and a solution of 2.0 g (7.18 mmol) of 3-methyl-1-(3-oxobutyl)-7-propylxanthine in 30 ml of tetrahydrofuran was added. The slightly exothermic reaction was complete after 30 minutes. The mixture was adjusted to pH 5-6 with 1 N hydrochloric acid and partitioned between dichloromethane and water. The organic phase was washed with water, dried with magnesium sulfate and concentrated under reduced pressure. The oily crude product was purified by flash chromatography, dichloromethane/methanol =19/0.75.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][CH2:24][CH2:25]C(O)=O.[N:29]1[CH:34]=CC=CC=1>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][CH2:24][CH2:25][N:29]=[C:34]=[O:8]
Reactant: c1ccncc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCc1cccs1
Product: O=C=NCCCc1cccs1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Diphenyl phosphoryl azide [N3.PO(OC6H5)] (9.08 g.) was added dropwise to a solution of 4-(2-thienyl)butyric acid (5.53 g.) in dry pyridine (25 ml.) and stirred for one hour at 100° C. to give a solution comprising 3-(2-thienyl)propyl isocyanate (I.R.: 2260 cm-1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([CH2:16]Cl)=O.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]3[CH2:39][O:38][C:37]([CH3:41])([CH3:40])[O:36]3)=[CH:29][CH:28]=2)[C:22]([C:42]#[N:43])=[C:21]([SH:44])[N:20]=1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]3[CH2:39][O:38][C:37]([CH3:40])([CH3:41])[O:36]3)=[CH:29][CH:28]=2)[C:22]([C:42]#[N:43])=[C:21]([S:44][CH2:16][C:14]2[N:11]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:10][CH:13]=2)[N:20]=1
Reactant: NC(=S)Nc1ccc(F)cc1
Reactant: CC1(C)OCC(COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1(C)OCC(COc2ccc(-c3c(C#N)c(N)nc(SCc4csc(Nc5ccc(F)cc5)n4)c3C#N)cc2)O1

Procedure:
102 mg (0.6 mmol) of 4-fluorophenylthiourea and 73.6 mg (0.58 mmol) of 1,3-dichloroacetone are dissolved in 2.5 ml of ethanol, and the mixture is stirred under reflux for 60 min. The mixture is allowed to cool and concentrated using a rotary evaporator. The residue is taken up in 1.5 ml of DMF, 153 mg (0.4 mmol) of the compound from Example 3A and 101 mg (1.2 mmol) of sodium bicarbonate are added and the reaction solution is stirred at RT for a further 16 h. The reaction mixture is purified directly by preparative HPLC chromatography (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[Cl:9][C:10](Cl)(Cl)[C:11]([Cl:15])=[C:12](Cl)[Cl:13].[Cl:18]C(Cl)=C(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:10]([Cl:9])=[C:11]([Cl:15])[CH:12]2[Cl:13])=[C:4]([Cl:18])[C:3]=1[Cl:8]
Reactant: Clc1ccccc1Cl
Reactant: ClC(Cl)=C(Cl)C(Cl)(Cl)Cl
Reactant: ClC(Cl)=C(Cl)Cl
Product: ClC1=C(Cl)C(Cl)c2cc(Cl)c(Cl)c(Cl)c21
Temperature: 125 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
A mixture containing 29.4 grams (0.2 mole), of ortho-dichlorobenzene, 50 grams (0.2 moles) of hexachloropropylene and 2.5 grams of ferric chloride in 250 milliliters of perchloroethylene was heated and stirred by the process of Example I for about 4 hours at reflux (125° C.). The reaction mixture was then washed with concentrated hydrochloric acid, then water and distilled to give a 48.7% yield of hexachloroindene. The product was confirmed by infrared and NMR spectra analysis as structured.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.FC(F)(F)S(O[Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])(=O)=O.CC1C=CC=C(C)N=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:17])=[CH:12][C:13]([O:16][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:15]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COc1ccc(F)c(-c2ccc(O)cc2O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxybiphenyl-2,4-diol (10.6 g) in toluene (80 mL) were added triisopropylsilyl trifluoromethanesulfonate (18 mL) and 2,6-dimethylpyridine (8.0 mL) at −15° C., and the mixture was stirred for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.5 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:15].[Li]CCCC.CCCCCC.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:15])=[CH:7][CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[C:10]=1[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: COCOc1ccc(C)c(OCOC)c1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(OCOC)ccc(C)c1OCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of 2,4-bis(methoxymethoxy)-1-methyl-benzene (Intermediate 7, 5.5 g, 25.94 mmol) in dry tetrahydrofuran (50 ml) at room temperature BuLi 1.6M in hexane (19.45 ml, 31.13 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chlorooxoacetate (4.35 ml, 38.9 mmol) in dry tetrahydrofuran (30 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with water (20 ml), diluted with brine (50 ml) and extracted with ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluent affording the title compound (4.65 g) as a light yellow oil.