Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
To 720 g of polyphosphoric acid (116.5%) heated at 90° C. were added 1.2 g of 2,5di(sulfamoylanilino)terephthalic acid followed by 120 g of 2,5-di(4-chloroanilino)terephthalic acid over a period of approximately 45 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The reaction mixture was held at 113° C. of five hours and then cooled to 95° C. To this mixture was added 89.4 g of phosphoric acid (75%) dropwise over a period of 20 minutes. The resultant melt was allowed to stir for 15 minutes at 92° C. and then poured slowly into 1240 g of methanol, the temperature being maintained below reflux by adjustment of the addition rate. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 105 g of 2,9-dichloroquinacridone as a magenta pigment.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[C:16]([C:18](O)=[O:19])[C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:14][C:10]=2[C:11](O)=[O:12])=[CH:4][CH:3]=1>O>[CH:3]1[C:2]([Cl:1])=[CH:7][C:6]2[C:11]([C:10]3[C:9]([NH:8][C:5]=2[CH:4]=1)=[CH:17][C:16]1[C:18]([C:27]2[CH:26]=[C:25]([Cl:28])[CH:24]=[CH:23][C:22]=2[NH:21][C:15]=1[CH:14]=3)=[O:19])=[O:12]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Solvent: O
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Yield: 101.6 %

Procedure:
2,5-Bis{(4-chlorophenyl)amino}terephthalic acid (3.35 gm; 8 mmol) and polyphosphoric acid (30 gm) were heated at 150° C. for 3 hours under a nitrogen atmosphere. The mixture was allowed to cool and then poured into iced water (200 ml) when a magenta solid precipitated out. This was filtered off, washed with water and methanol, then dried under vacuum over phosphorous pentoxide to give 3.1 gm (100%) of 2,9-dichloroquinacridone.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24][C:25]([N:27]([C@H:29]([CH3:38])[C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:28])=[O:26])[CH:19]=[CH:20][C:21]=1[S:22][CH3:23].I[CH2:40][C@@H:41]1[CH2:61][CH2:60][C:43]2([O:47][C@@H:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:44]2)[CH2:42]1.N1C=CC=NC1=O.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:24]([CH2:40][C@@H:41]2[CH2:61][CH2:60][C:43]3([O:47][C@@H:46]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C@H:45]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[O:44]3)[CH2:42]2)[C:25]([N:27]([C@H:29]([CH3:38])[C@H:30]([OH:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:28])=[O:26])[CH:19]=[CH:20][C:21]=1[S:22][CH3:23]
Reactant: CSc1ccc(CC(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1Cl
Reactant: IC[C@@H]1CCC2(C1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=c1nccc[nH]1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CSc1ccc([C@@H](C[C@@H]2CCC3(C2)O[C@@H](c2ccccc2)[C@H](c2ccccc2)O3)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1Cl
Temperature: -7 °C
Reaction time: 0.08 h
Yield: 102.1 %

Procedure:
A solution of 1,1,1,3,3,3-hexamethyldisilazane (3.18 mL, 15.05 mmol) in tetrahydrofuran (20 mL) cooled to −20° C. was treated with a 2.5M solution of n-butyllithium in hexanes (5.8 mL, 14.5 meq) over 10 min at such a rate as to keep the temperature below −15° C. The mixture was stirred for an additional 5 min. The cold reaction mixture was then treated with a solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-N-(2(R)-hydroxy-1(R)-methyl-2-phenyl-ethyl)-N-methylacetamide (prepared as in Example 30, 2.77 g, 7.61 mmol) in tetrahydrofuran (22 mL) via syringe over 8 min, at such a rate as to keep the temperature below −15° C. The reaction was then slowly allowed to warm to −7° C. over 20 min and then a solution of 7(R)-iodomethyl-2(S),3(S)-diphenyl-1,4-dioxa-spiro[4.4]nonane (2.42 g, 5.76 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2)(1H)-pyrimidinone (1.7 mL, 14.1 mmol) in tetrahydrofuran (10 mL) was added over 6 min. An exotherm increased the temperature to −4° C. during the addition. The reaction was allowed to warm to 0° C., where it was stirred for an additional 3 h. At this time, the reaction was poured into a mixture of toluene (70 mL) and a 20% aqueous ammonium chloride solution (50 mL, 187 mmol) and was then stirred vigorously. The organic layer was separated and re-washed with a 20% aqueous ammonium chloride solution (50 mL, 187 mmol). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-(2(S),3(S)-diphenyl-1,4-dioxa-spiro [4.4]non-7(S)-yl)-N-(2(R)-hydroxy-1(R)-methyl-2-phenyl-ethyl)-N-methyl-propionamide (3.86 g) as an overweight brown semi-solid. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-(2(S),3(S)-diphenyl-1,4-dioxa-spiro[4.4]non-7(S)-yl)-N-(2(R)-hydroxy-1(R)-methyl-2-phenyl-ethyl)-N-methylpropionamide as a yellow foam (2.28 g, 60.4%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>C(OCC)(=O)C>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:14]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=C(CCl)CCl
Solvent: CCOC(C)=O
Product: ClCc1coc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Benzamide (1.21 g, 10 mmol) is mixed with 1,3-dichloroacetone (1.26 g, 10 mmol) and the mixture heated to 130° C. and stirred at this temperature for 1 h. The resulting mixture is then cooled, diluted with ethyl acetate, washed with K2CO3 solution (sat.), then brine, dried over MgSO4 and concentrated to give the title compound as a solid, which is used without further purification. MS (ESI) 194 (M+H, Cl pattern)+.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]2[CH:12]=[CH:13][CH:14]=[C:3]12.[B].CSC>>[S:9]1[C:7]2[NH:8][CH2:2][C:3]3[N:4]([CH:12]=[CH:13][CH:14]=3)[CH2:5][C:6]=2[CH:11]=[CH:10]1
Reactant: O=C1Nc2sccc2Cn2cccc21
Agent: [B]
Solvent: CSC
Product: c1cc2n(c1)Cc1ccsc1NC2

Procedure:
The synthesis of 9,10-dihydro-4H-furo[2,3-e]-pyrrolo[1,2-a][1,4]diazepin-9-one ##STR81## is reported by F. Povazunec, B. Decroix and J. Morel, J. Het. Chem. 29, 1507(1992) and is reduced to give the tricyclic heterocycle 9,10-dihydro-4H-furo[2,3-e]-pyrrolo[1,2-a][1,4]diazepine. ##STR82## The tricyclic 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]-benzodiazepine ring system is reported by L. Cecchi and G. Filacchioni, J. Het. Chem., 20, 871(1983); ##STR83## The synthesis of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]-thieno[2,3-e][1,4]diazepine is reported by A. Daich and B. Decroix, Bull. Soc. Chim. Fr 129, 360(1992); ##STR84## and is reduced with boron-dimethylsulfide to give 9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. ##STR85## Also reported by A. Daich and B. Decroix is 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine ##STR86## which is also reduced to give 4,10-dihydro-5H-pyrrolo-[1,2-a ]thieno[3,2-e][1,4]diazepine ##STR87## Reported by B. Decroix and J. Morel, J. Het. Chem., 28, 81(1991) are pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine; ##STR88## and pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. Reduction by hydrogen-Pd/c or chemical reduction with reagents such as sodium cyanoborohydride and acetic acid gives the dihydro tricyclic heterocycles ##STR89## The synthesis of the tricyclic 1,5-benzodiazepine ring system, 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine, has been reported by F. Chimenti, S. Vomero, R. Giuliano and M. Artico, IL Farmaco, Ed. Sc., 32, 339(1977). Annelated 1,5-benzodiazepines containing five membered rings have been reviewed by A. Chimirri, R. Gitto, S. Grasso, A. M. Monforte, G. Romeo and M. Zappala, Heterocycles, 36, No. 3, 604(1993), and the ring system 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine is described. ##STR90##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cccc(CBr)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Ethyl (3-methylphenyl)acetate (5.36 g) was mixed with carbon tetrachloride (80 ml), followed by heating at 90° C. N-Bromosuccinimide (5.62 g) and α,α′-azobisisobutyronitrile (250 mg) were added thereto, followed by stirring at 90° C. for 5 hours. The reaction mixture was cooled to room temperature, and then the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl [3-(bromomethyl)phenyl]acetate (4.56 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH2:12][C:13]([NH2:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([NH2:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)CI
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 74.7 %

Procedure:
A mixture of 4-nitrophenol (7.5 g), iodoacetamide (10 g), potassium carbonate (7.5 g) and dimethylformamide (50 ml) was stirred at 50° C. for 15 hours. The mixture was poured into ice-water, and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from acetone-diisopropyl ether to give the desired compound (7.9 g) as colorless crystals.
Reaction SMILES: NC1N=CSC=1.Br[C:8]1[S:9][CH:10]=[C:11]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[N:12]=1>>[F:18][C:15]([F:16])([F:17])[C:14]([NH:13][C:11]1[N:12]=[CH:8][S:9][CH:10]=1)=[O:19]
Reactant: O=C(Nc1csc(Br)n1)C(F)(F)F
Agent: Nc1cscn1
Product: O=C(Nc1cscn1)C(F)(F)F

Procedure:
The method of preparing 4-aminothiazole comprising reacting 2-bromo-4-trifluoroacetamidothiazole under low pressure catalytic hydrogenation conditions in the presence of a noble metal catalyst to give 4-trifluoroacetamidothiazole then reacting said 4-trifluoroacetamidothiazole with sodium or potassium hydroxide in an aqueous medium at from about 30°-35°C. for about 4-8 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(NC(C)C)(C)C.[Li].[CH:19]1([CH:24]=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH:19]1([CH:24]([C:7]2[C:2]([Cl:1])=[N:3][C:4]([S:9][CH3:10])=[N:5][C:6]=2[Cl:8])[OH:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CC1CCCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1nc(Cl)c(C(O)C2CCCC2)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine (8.0 g, 41.01 mmol) was dissolved in 500 mL dry THF and cooled to −78° C. Lithium diisopropylamine (36.9 mL of 2.0 M solution in hexanes) was added dropwise, and the reaction mixture was stirred for 20 minutes at −78° C. Cyclopentane-carboxaldehyde (8.05 g, 82.02 mmol was added, and the reaction mixture was stirred for 45 minutes at −78° C. The reaction was quenched by addition of saturated aqueous ammonium chloride. The aqueous mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (5% to 40% EtOAc in hexanes) to yield 9.76 g of cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanol. Mass Spec. M+H=294.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(O)(C)C>ClCCl>[CH3:24][S:25]([O:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 73.3 %

Procedure:
3,3-diphenyl-1-propanol (1000 g, 4.7 mol) was dissolved in 3 L dichloromethane. To the mixture was added triethylamine (712 g, 7.05 mol). After stirring at 0° C. for half an hour, to the resulting mixture was slowly added MsCl (645 g, 5.64 mol) dropwisely. The reaction was conducted at 25° C. After the completion of reaction monitored by TLC, the reaction solution was washed with water thrice. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce an oily crude product. To the crude product was added isopropanol. The resulting mixture was filtered by suction to produce 3,3-diphenylpropyl methanesulfonate as a solid (1000 g) in a yield of 73% (two steps together).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].CO.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
In 15 mL of methylene chloride was dissolved 5.44 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate followed by addition of 54 mL of methanol and 8.2 mL of 1N-HCl, and the mixture was stirred at 25° C. for 2 hours. Then, 19 mL of water and 19 mL of ethyl acetate were added and the mixture was adjusted to pH 3.2 with a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted using 19 mL of water and 54 mL of ethyl acetate and the aqueous layer was separated and extracted with 30 mL of ethyl acetate. The organic layers were combined, washed with 40 mL of water and concentrated under reduced pressure to give an oil. This oil was purified by silica gel chromatography (300 mL, methylene chloride-methanol=10:1) to provide 2.92 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate (yield 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].Cl.C(=O)([O-])O.[Na+].[Na+].[Cl-].O>C(Cl)Cl.C(OCC)(=O)C.O.CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
In 29 mL of methylene chloride was dissolved 10.00 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate followed by addition of 23 mL of methanol and cooling to 5° C. Then, 6 mL of methanol containing 0.53 g of hydrogen chloride as dissolved was added dropwise at 5° C. over a period of 15 minutes. The mixture was further stirred at 5° C. for 3.5 hours, at the end of which time 19 mL of ethyl acetate and 19 mL of water were added. The mixture was adjusted to pH 6.3 with a saturated aqueous solution of sodium hydrogen carbonate and, then, 10 mL of ethyl acetate and 10 mL of 20% NaCl-H2O were added. The aqueous layer was separated and extracted with 20 mL of ethyl acetate. The ethyl acetate layers were combined and redistributed into 20% NaCl and 38 mL of ethyl acetate. The organic layer was separated and concentrated and the residue was diluted with ethanol and reconcentrated. To the residue was added 20 mL of acetone and the mixture was stirred at room temperature for 3 hours for sufficient crystallization. Thereafter, 90 mL of hexane was added and the mixture was further stirred at room temperature for 1 hour and, then, under ice-cooling for 2 hours. The resulting crystals were collected by filtration and washed with 25 mL of acetone-hexane (1:9). The crystals were dried under reduced pressure to provide 6.90 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methylbenzimidazole-7-carboxylate (yield 92%).
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([F:15])[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[C:4]([CH:20]=[O:21])[CH:3]=1.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:22]1([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)=[C:6]([F:15])[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[C:4]([CH:20]=[O:21])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Yield: 90.9 %

Procedure:
A mixture of 6-bromo-2,4′-difluoro-3-isopropoxybiphenyl-4-carbaldehyde (2.94 g), cyclopropylboronic acid (1.42 g), tris(dibenzylideneacetone)dipalladium(0) (0.531 g), a 2 M aqueous sodium carbonate solution (12.4 mL), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.510 g), and toluene (30 mL) was stirred overnight at 100 C in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and water and then filtered through celite. The organic layer was separated from the filtrate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.38 g).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[N:2]1.Br[CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:11]
Reactant: CCOC(=O)C(C)(C)CBr
Reactant: N#Cc1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2c(C#N)cccc21
Reaction time: 7 h
Yield: 37 %

Procedure:
1H-Indazole-4-carbonitrile (commercially available from Insight Chemical Solutions Ltd.) (500 mg, 3.49 mmol), ethyl 3-bromo-2,2-dimethylpropanoate (D98) (803 mg, 3.84 mmol) and Cs2CO3 (1.36 g, 4.19 mmol) in dry DMF (3 ml) was heated to 80° C. overnight and then for a further 7 hours. The reaction mixture was then partitioned between EtOAc and H2O. The two layers were separated and the organic phase was washed with more H2O, brine, dried and concentrated a yellow oil. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (356 mg, 37%) as a crystalline material. MS (ES) C15H17N3O2 requires 271, found 272 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[B:15](OC)([O:18]C)[O:16]C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([B:15]([OH:18])[OH:16])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Clc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1Cl
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
4-Bromo-1-chloro-2-iodobenzene (10.35 g, 33 mmol) is dissolved in anhydrous tetrahydrofuran (60 ml) and the solution is cooled to −75° C. under an atmosphere of argon. Isopropylmagnesium chloride (17.1 ml, 34 mmol, 2M solution in tetrahydrofuran) is added dropwise over 30 minutes, maintaining the internal temperature below −70° C. by external cooling. Once the addition is complete, the reaction mixture is stirred at approximately −70° C. for 30 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is then cooled to −78° C. and trimethyl borate (7.3 ml, 65 mmol) is added dropwise. The mixture is stirred at −78° C. for 30 minutes and then the cooling bath is removed and the mixture stirred at room temperature for 1.5 hours. 2M Aqueous hydrochloric acid (30 ml) is added, and the crude product is then extracted with ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Trituration with hexane gives 5-bromo-2-chlorophenylboronic acid (6.16 g) as an off-white solid.