Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[C:8]2[CH:12]=[C:11]([CH:13]=[O:14])[S:10][C:9]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]([Mg]Br)([CH3:30])[CH3:29].O1CCCC1.[Cl-].[NH4+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C(Cl)Cl>[CH:1]1([CH:7]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[C:8]2[CH:12]=[C:11]([C:13](=[O:14])[CH:28]([CH3:30])[CH3:29])[S:10][C:9]=2[CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[Mg]Br
Reactant: CCc1sc(C=O)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1sc(C(=O)C(C)C)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of methyl 4-{[cyclohexyl(2-ethyl-5-formylthiophen-3-yl)methyl]amino}benzoate (400 mg) synthesized above in tetrahydrofuran (10 mL) was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (1.25 mL) at 0° C., and the mixture was stirred for 1 hr under a nitrogen atmosphere. 1.0M Isopropylmagnesium bromide-tetrahydrofuran solution (1.25 mL) was added dropwise again, and the mixture was further stirred at 0° C. for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give a yellow oil. To a solution of the obtained oil in methylene chloride (10 mL) was added Dess-Martin reagent (662 mg) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous sodium sulfite solution was added to quench the reaction, methylene chloride was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give the title compound (268 mg, 60%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:22])=[CH:4][N:3]=1.[N+:23]([C:26]1[CH:27]=[N:28][NH:29][CH:30]=1)([O-:25])=[O:24].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.[Cu](I)I.O.C(OCC)(=O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([N:28]3[CH:27]=[C:26]([N+:23]([O-:25])=[O:24])[CH:30]=[N:29]3)=[N:3][CH:4]=[C:5]([Cl:22])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc([N+](=O)[O-])cn2)cc1

Procedure:
A solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzene sulfonamide (534 mg, 1.32 mmol), 4-nitropyrazole (224 mg, 1.98 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (42 L, 0.264 mmol), copper iodide (51 mg, 0.264 mmol), and cesium carbonate (903 mg, 2.77 mmol) in 5 mL of N,N-dimethylacetamide was heated at 130° C. for 2 hours. Ethyl acetate and water were added and the layers were separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude reside was subsequently purified by flash column chromatography (0-100% ethyl acetate in hexanes) to afford 4-tert-butyl-N-[5-chloro-2-(4-nitro-pyrazol-1-yl)-pyridin-3-yl]-benzenesulfonamide as a white solid.
Reaction SMILES: B.C(SCCC(C)C)CC(C)C.CC1(C)[C@H]2C[C@@H]1CCC2=C.[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+].C(SCCC(C)C)CC(C)C.[CH3:44][C:45]1([CH3:54])[C@@H:50]2[CH2:51][C@H:46]1[CH2:47][CH2:48][C@@H:49]2[CH2:52][OH:53]>C1COCC1>[CH3:44][C:45]1([CH3:54])[C@H:50]2[CH2:51][C@@H:46]1[CH2:47][CH2:48][C@H:49]2[CH2:52][OH:53]
Reactant: CC1(C)[C@@H]2CC[C@H](CO)[C@H]1C2
Agent: B
Agent: C=C1CC[C@H]2C[C@@H]1C2(C)C
Agent: CC(C)CCSCCC(C)C
Solvent: C1CCOC1
Product: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Borane-diisoamyl sulfide (5.0 ml, 21 mmol) was dissolved in THF (20 ml) and (-)-β-pinene (8.86 g, 64 mmol), [α]23D=-20.8° (neat), 91% ee, was added at 0° C. The mixture was kept at room temperature for 1 h and oxidized by the addition of 3M sodium hydroxide (10 ml, 30 mmol) and 30% hydrogen peroxide (7 ml, 70 mmol) keeping the temperature during the addition below 30° C. and then stirring at room temperature for 3 h. The mixture was saturated with potassium carbonate, the THF layer was separated and the aqueous layer was extracted with diethyl ether (2×50 ml). The extracts were combined with the THF solution, dried over magnesium sulfate and distilled using a Widmer column to give a first fraction, 4.25 g, bp 45°-58° C./0.1 mm Hg composed of diisoamyl sulfide (77%) and cis-myrtanol (23%) and a second fraction 7.96 g (82%), bp 58°-60° C./0.1 mm Hg, n20D=1.4907, [α]°D=-19.4° (neat).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[CH2:21][N:22]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH3:24])[CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester and benzyl chloroformate were reacted as described in Example 11, Step 2 to provide (5-{2-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([O:16]C)[C:13]([C:18]#[N:19])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([OH:16])[C:13]([C:18]#[N:19])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(OC)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(O)c(C#N)c2)cc1
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of 4-(3-cyano-4-methoxypyrrole-1-yl)benzoic acid ethyl ester (0.081 g) in dichloromethane (3 mL) was added boron tribromide (0.33 mL, 1 mol/L dichloromethane solution) under ice-cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water, and this mixture was extracted with diethyl ether. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/1) to give 4-(3-cyano-4-hydroxypyrrole-1-yl)benzoic acid ethyl ester (0.052 g). To a solution of 4-(3-cyano-4-hydroxypyrrole-1-yl)benzoic acid ethyl ester (0.052 g) in N,N-dimethylformamide (4 mL) were added benzylbromide (0.038 g) and cesium carbonate (0.13 g) at room temperature, and this mixture was stirred at 80° C. for 5 hours. To this reaction mixture was added water at room temperature, and the precipitated solid was collected by filtration, and washed with methanol (5 mL) to give the title compound (0.016 g).
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@H:2]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[OH:23][C:24]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)=[O:35])[CH2:27][CH2:26]1.O.OO>O1CCCC1>[OH:23][C:24]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH3:48])([CH3:47])[C:43]([O:45][CH2:46][CH3:2])=[O:44])=[CH:38][CH:37]=2)[OH:35])[CH2:27][CH2:26]1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@@H]([C@H]1C)C3(C)C)C2(C)C
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1ccc([C@@H](O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve (-)-B-chlorodiisopinocamphenylborane (2.5 g, 7.8 mmol) in anhydrous tetrahydrofuran (5 mL). Add a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid, methyl ester (3.54 mmol) in anhydrous tetrahydrofuran (5 mL). Stir at room temperature for 3 days and cool to 0° C. Add water (1 mL) and 30% hydrogen peroxide (2 mL) and stir for 20 minutes. Add methylene chloride (30 mL) and wash with brine (30 mL), then aqueous sodium hydrogen carbonate (30 mL), then brine (30 mL). Dry (MgSO4), evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.Cl>[OH-].[K+]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2
Reactant: CCOC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
22 G. of 5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is stirred in 200 ml. of chloroform, 50 ml. of thionyl chloride and 1 ml. of dimethylformamide for 8 hrs. The mixture is evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptene. This is dissolved in 200 ml. of chloroform and added to a 3-fold excess of ethereal diazomethane at 0°C. The mixture is left at 0°C for 12 hrs. then evaporated to dryness. The residue is recrystallized from acetonitrile to yield 2-diazoacetyl-5-oxo-5H-dibenzo-[a,d]cycloheptene. The diazoketone is heated to reflux in 250 ml. of ethanol and a saturated triethylamine solution of 2 g. of silver benzoate is added slowly until gas evolution ceases. The solution is cooled, filtered and evaporated to yield ethyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetate. This ester is refluxed in 5% aqueous potassium hydroxide for 12 hrs. The solution is cooled, acidified with dilute hydrochloric acid and extracted with ether. The ether extract is dried and evaporated to yield (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid which can be recrystallized from acetone-hexane (m.p 148°-149.5°C).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([CH3:24])[CH:15]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][CH:26]([F:37])[O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[F:25][CH:26]([F:37])[O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[C:16]([CH3:24])[CH:15]=4)[CH2:12][O:11][C:10]([NH2:13])=[N:9]3)[CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1cccc(OC(F)F)c1
Reactant: Cc1cc(C2(c3cccc(Br)c3)COC(N)=N2)ccc1OC(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1cc(C2(c3cccc(-c4cccc(OC(F)F)c4)c3)COC(N)=N2)ccc1OC(F)F
Temperature: 100 °C
Yield: 31.1 %

Procedure:
A dried pressure tube was charged with (RS)-4-(3-bromo-phenyl)-4-(4-difluoromethoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block S) (131 mg, 0.3 mmol), 3-(difluoromethoxy)-benzeneboronic acid (93 mg, 0.5 mmol), triphenylphosphine (18 mg, 0.1 mmol), 2 N sodium carbonate solution (0.5 mL), and 1,2-dimethoxyethane (3 mL). The mixture was purged with nitrogen before palladium(II) acetate (7 mg, 0.03 mmol) was added. The sealed pressure tube was heated at 100° C. for 15 hours. For the working-up, the reaction mixture was cooled and evaporated under reduced pressure. The residue was directly chromatographed on silica gel using a gradient of dichloromethane/methanol=100/0 to 95/5 as the eluent. There were obtained 43 mg (28% of theory) of (RS)-4-(3′-difluoromethoxy-biphenyl-3-yl)-4-(4-difluoromethoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine as light yellow solid. Mass (calculated) C24H20F4N2O3 [460]; (found) [M+H]+=461.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:8]=2[N:9]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)#[N:2]
Reactant: [C-]#N
Reactant: CCNc1ccc2nc(Cl)sc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNc1ccc2nc(C#N)sc2c1
Temperature: 120 °C

Procedure:
Potassium cyanide (18 mg) and 2-chloro-6-ethylaminobenzothiazole (18 mg) were dissolved in 1 ml DMSO and heated to 120° C. for 4 h. After cooling to room temperature, the reaction was poured into 0.2M potassium phosphate, pH 4.5. The aqueous layer was extracted with ethyl acetate three times, washed with water, and dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by silica gel chromatography (20% ethyl acetate in hexanes). 1H-NMR (d6-DMSO): δ 7.85 (d, 1H, J=9.2 Hz), 7.13 (d, 1H, J=2.4 Hz), 6.98 (dd, 1H, J=2.4, 8.8 Hz), 6.44 (br t, 1H), 3.09 (m, 2H), 1.18 (t, 3H, J=7.2 Hz).
Reaction SMILES: CS(O[CH2:6][C:7]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:8])(=O)=O.[N-:57]=[N+:58]=[N-:59].[Na+].CN(C)C=O>O>[N:57]([CH2:6][C:7]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:8])=[N+:58]=[N-:59]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(COCCCCCCCCCCCCCCCCCCCCCC)COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(CN=[N+]=[N-])COCCCCCCCCCCCCCCCCCCCCCC
Temperature: 110 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
After a mixture of 2,2-bis(docosyloxymethyl)propyl methanesulfonate (22.7 g; 27.8 mmol), sodium azide (0.27 g; 83.5 mmol), and dimethylformamide (150 ml) was stirred at 110° C. for 20 h, the reaction mixture was poured into water. Precipitates thus obtained were collected by suction, washed successively with water and acetone, and dried to obtain the title compound (20.8 g; 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:5]([NH2:20])=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:20][C:21](=[O:22])[N:8]([CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])[C:6]=2[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)[nH]c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
5-Bromo-N1-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine (1.8 g, 5.14 mmol) was dissolved in dry THF (50 mL) and 1,1′-carbonyl-diimidazole (0.92 g, 5.65 mmol) was added. The dark brown solution was stirred at room temperature under nitrogen overnight. The mixture was diluted with ethyl acetate and washed with water then brine and dried over anhydrous magnesium sulfate. After filtration and concentration the crude product was chromatographed on silica gel eluting with 5-50% ethyl acetate in hexanes to give 6-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-benzo[d]imidazol-2(3H)-one as a purple oily foam (1.14 g, 2.96 mmol).
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18](=[O:19])[N:17]([CH:20]3[CH2:22][CH2:21]3)[C:16]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:15]2)=[C:9]([Cl:30])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:30][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[CH2:13][N:14]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:22][CH2:21]2)[C:16]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[N:15]1)[C:6]([OH:31])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
An amount of 1.38 g (3.00 mmol) of the compound from Example 26A was dissolved in 10 ml of dichloromethane and admixed at RT with 3.0 ml (39 mmol) of trifluoroacetic acid and stirred at RT for 72 h. The mixture was concentrated under reduced pressure and admixed with 10 ml of toluene and concentrated again. This procedure was repeated a further two times. The residue which remained was freed from remnants of solvent under a high vacuum. This gave 1.27 g (63% of theory) of the target compound with a purity of 60%.
Reaction SMILES: [OH:1][P:2]([O:4][P:5]([OH:7])[OH:6])[OH:3].Cl[C:9](Cl)([C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])[OH:10].C1(C)C=CC=CC=1>C(N(CC)CC)C>[OH:1][P:2]([O:4][P:5]([OH:7])[OH:6])[OH:3].[OH:10][CH2:9][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13]
Reactant: OCC(CO)(CO)C(O)(Cl)Cl
Agent: OP(O)OP(O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCC(CO)(CO)CO

Procedure:
Dichloro pentaerythritol diphosphite (1 mol) was reacted with 2.05 mol of Abitol in toluene using 2.1 mol of triethyl amine as an acid acceptor. The very viscous liquid product, bis abietyl pentaerythritol diphosphite, was obtained after filtering the triethylamine hydrochloride and stripping the toluene.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[CH:12]=[C:11]([O:13]COC)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].Cl.C(O)C>O>[F:1][CH:2]([F:17])[C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCOc1ccc(C(=O)OC)c(C(F)F)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(O)cc1C(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To methyl 2-(difluoromethyl)-4-(methoxymethoxy)benzoate (720 mg) were added 2N hydrochloric acid (6 ml) and ethanol (6 ml), and the mixture was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, and water was added thereto, and extracted with ethyl acetate. To the extract was added a saturated aqueous sodium chloride solution, and the mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (500 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([N:9]2[CH:10]=[C:6]([CH2:4][OH:3])[CH:7]=[N:8]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnn(S(=O)(=O)c2ccc(C)cc2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(CO)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a chilled (−78° C.) solution of 1-(toluene-4-sulfonyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.90 g, 3.06 mmol) in CH2Cl2 was added a 1 M solution of DIBAH (11.00 mL, 11.00 mmol) in CH2Cl2 dropwise. After 4 hours, the reaction was warmed to room temperature. After 8 hours, the mixture was diluted with saturated aqueous NaHCO3. After 2 hours, the solution was passed through the diatomaceous earth. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the [1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-methanol.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([SH:10])[N:7]=[C:6]([OH:11])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[CH2:2][CH3:3].[OH-].[K+].[CH3:29]I>CO>[CH2:1]([C:4]1[N:9]=[C:8]([S:10][CH3:29])[N:7]=[C:6]([OH:11])[C:5]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: CI
Reactant: CCCc1nc(S)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc(SC)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
26 g of 6-n-propyl-2-mercapto-4-hydroxy-5[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 100, are stirred for 15 minutes in a solution of 5 g of potassium hydroxide in 100 ml of methanol. 6 ml of methyl iodide are added to the mixture, which is then stirred for 4 hours at room temperature. The crystals formed are drained, washed with water and then with ether and dried to give 23 g of 6-n-propyl-2-methylthio-4-hydroxy-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine in the form of crystals of melting point 218° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:44](=[O:45])[C:43]2[CH:47]=[CH:48][C:40]([CH2:39][N:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4([CH2:31][O:30][C:29]5[CH:32]=[C:33]6[C:37](=[CH:38][C:28]4=5)[CH2:36][CH2:35][O:34]6)[C:19]3=[O:18])=[CH:41][CH:42]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Cc1c(N)cccc1F
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1c(F)cccc1NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 3-fluoro-2-methylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-fluoro-2-methylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (35%) as a colorless solid: mp 143-144° C.; 1H NMR (300 MHz, CDCl3) δ 7.91-7.84 (m, 2H), 7.74-7.64 (m, 2H), 7.52-7.45 (m, 2H), 7.29-7.17 (m, 3H), 7.10-7.02 (m, 1H), 6.96-6.87 (m, 1H), 6.80-6.74 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.04 (ABq, 2H), 4.85 (ABq, 2H), 4.60-4.51 (m, 2H), 3.10-2.91 (m, 2H), 2.23 (d, J=1.51 Hz, 3H); MS (ES+) m/z 521.0 (M+1).