Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16].C([O-])(O)=O.[Na+].O>CO>[CH2:2]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])[C:3]1([O:12][CH2:11][C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6])[OH:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@H](C)[C@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
30 g of anhydrous D-glucose were dissolved together with 3 g of isoleucyl-aspartic acid in 1.2 l of methanol, and 200 mg of NaHCO3 were added. The mixture was subsequently heated under reflux for 2 hours. The water which had formed was then removed by distillation with butanol, and the reaction mixture was diluted with methanol and again heated for 2 hours. After completion of the reaction, solvent was removed from the solution in vacuo, and the residue, in 300 ml of water, was applied to a 600 ml-capacity chromatography column (diameter 5 cm) packed with QAE-®Sephadex A-25. Whereas the excess glucose was located in the fore-run, it was possible to obtain selectively N-(1-deoxyfructopyranos-1-yl)-isoleucylaspartic acid using an acetic acid gradient (0 to 0.5 molar). These eluates from the column were collected and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1.[CH:17]([O:20]C)(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:13][C:7]1[C:6]2[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3][C:2]([CH3:16])([CH3:1])[C:11]=2[CH:10]=[C:9]([CH3:12])[C:8]=1[CH:17]=[O:20]
Reactant: Cc1cc(C)c2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1C=O)C(C)(C)CCC2(C)C
Yield: 71.9 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1,1,4,4,5,7-hexamethylnaphthalene (5.0 g) of TiCl4 (7.32 g) in methylene chloride (40 ml) was treated with Cl2CHOCH3 (2.66 g) in methylene chloride (5 ml), at 0° and over 20 min. The temperature of the reaction mixture was allowed to reach 20° (20 min) and said mixture was then poured on ice water and extracted with ether. The organic phase was successively washed with a 10% aqueous solution of NaOH, water and an aqueous solution saturated with NaCl, then dried over Na2SO4, evaporated and recrystallized from methanol. 4.06 g (yield 72%) of 5,6,7,8-tetrahydro -1,3,5,5,8,8-hexamethyl-2-naphthalenecarbaldehyde were obtained, the product being identical in data to that described in b).
Reaction SMILES: C[O:2][C:3](=[O:29])[C@:4]1([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:8][C:7](=O)[CH2:6][N:5]1C(=O)NC1C=C(Cl)C=C(Cl)C=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@:4]2([C:3]([OH:29])=[O:2])[CH2:8][CH2:7][CH2:6][NH:5]2)=[CH:27][CH:26]=1
Reactant: COC(=O)[C@]1(Cc2ccc(Br)cc2)CC(=O)CN1C(=O)Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@]1(Cc2ccc(Br)cc2)CCCN1

Procedure:
means resin polymer.) (1) A mixture of N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline ethyl ester (3.00 g), LiOH (10 mmol), THF (25 mL), MeOH (10 mL) and H2O (5 mL) was stirred at room temperature overnight. The mixture was then heated at 74° C. overnight. The mixture was concentrated in vacuo, and water was added. The mixture was washed with Et2O and the aqueous layer was made acidic with the addition of 1N H2SO4. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, and evaporated to give N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (3.02 g). MS (m/z) 284 (MH+-t-Boc); mp: 143.9° C. (2) To a solution of the compound obtained above (2.45 g) in DMF (100 mL) was added Merrifield Resin (4.70 g) and KF (1.1 g). The resulting mixture was stirred under N2 at 80° C. overnight. The resin was filtered, and washed thoroughly with MeOH, H2O and CH2Cl2, then dried in vacuo overnight to yield the resin-bound N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (6.66 g); FTIR (cm−1) 1740, 1697, 1397, 1131, 1011. (3) The compound obtained above was then deprotected using a 50% solution of TFA in CH2Cl2, followed by thorough washing, to give the resin-bound 2-(4-bromobenzyl)proline (6.09 g); FTIR (cm−1) 1722. (4) To the compound obtained above (200 mg) was added a DMF solution of 2,6-dichloro-4-pyridyl isocyanate (5 equiv.). This mixture was shaken at room temperature in a sealed receptacle overnight. The mixture was filtered, and the resin was washed with DMF, water and MeOH, and air-dried to give the resin-bound N-[(2,6-dichloro-4-pyridyl)carbamoyl]-2-(4-bromobenzyl)proline. (5) A solution of DIEA (350 μL) in DMF (5 mL) was added to the compound obtained above, and the resulting mixture was then shaken at 50° C. for 2 hours, then at room temperature overnight. The resin was filtered and washed with MeOH, and the filtrate was evaporated. The residue was purified by reverse phase HPLC (gradient of 0%-70% CH3CN in water) to yield 3-(2,6-dichloro-4-pyridyl)-5-(4-bromobenzyl)-1,3-diazabichclo[3.3.0]octane-2,4-dione (58.0 mg). MS (m/z): 456 (MH+); mp: 76.3° C.;
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][CH:4]([C:15]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1)[C:5](=[O:14])[C:6]1[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=1.[CH2:25]([Mg]I)[CH2:26][CH3:27]>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([C:5]([CH2:25][CH2:26][CH3:27])([OH:14])[CH:4]([CH2:3][C:2]([F:23])([F:24])[F:1])[C:15]2[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)C(CC(F)(F)F)c2ccc(OC)cc2)cc1
Reactant: CCC[Mg]I
Product: CCCC(O)(c1ccc(OC)cc1)C(CC(F)(F)F)c1ccc(OC)cc1

Procedure:
To an ethereal solution of n-propyl magnesium iodide (prepared from 0.07 molar n-propyl iodide and magnesium in 100 ml. ether) was added, while stirring, a solution of 16.9 g. (0.05 mole) α-trifluoroethyl-deoxyanisoin (see Example 1a)) and the reaction mixture was heated under reflux for 3 hours, whereafter it was poured into ice - dilute hydrochloric acid and extracted with ether. The ethereal extract was washed with water and an aqueous solution of sodium bisulphite, dried and evaporated to dryness. There was obtained an oily residue of 4,4'-dimethoxy-α-(n-propyl)-α-hydroxy-α'-trifluoroethyl-bibenzyl.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([C:20]#[N:21])=[C:7]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.[C:36]1([CH3:45])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.[F-].[Cs+]>COCCOC.CO.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:45])[C:7]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[C:8]2[C:20]#[N:21])=[CH:13][CH:14]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(Br)c32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(-c4ccccc4C)c32)cc1

Procedure:
To a mixture of EXAMPLE 581C (300 mg) and o-tolylboronic acid (93 mg) in 1,2-dimethoxyethane (10 ml) and methanol (5 ml) was added tetrakis(triphenylphosphine)palladium(0) (33 mg) and CsF (260 mg). The mixture was stirred at reflux under nitrogen for 4 hours. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (300 mL) and water (100 ml). The aqueous layer was further extracted with ethyl acetate and the combined extracts were washed with water, brine and dried over Na2SO4. After filtration, concentration of the solvent and column purification (5 to 10% ethyl acetate in hexane) gave EXAMPLE 581D.
Reaction SMILES: [C:1](=[S:19])([O:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)[NH2:2].Cl[CH2:21][C:22](=O)[CH3:23].O>C(O)(=O)C>[C:15]([C:6]1[CH:5]=[C:4]([O:3][C:1]2[S:19][CH:21]=[C:22]([CH3:23])[N:2]=2)[CH:9]=[C:8]([C:10]([CH3:11])([CH3:12])[CH3:13])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(OC(N)=S)cc(C(C)(C)C)c1O
Reactant: CC(=O)CCl
Solvent: CC(=O)O
Solvent: O
Product: Cc1csc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 58.7 %

Procedure:
O-(3,5-Di-tert-butyl-4-hydroxyphenyl) thiocarbamate (1.5 g) and 1.3 g of chloroacetone were dissolved in 60 ml of acetic acid, and the solution was heated at 90°-100° C. for 15 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product obtained was purified by silica gel column chromatography (diethyl ether-hexane =1:4) to give 1.0 g of the desired compound as a colorless solid.
Reaction SMILES: C1([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:9]([C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[N:8]2)C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:9]3[N:8]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:7]=[CH:11][C:10]=3[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[CH:19]=2)=[O:34])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cccc(-c2nn(-c3ccccc3)cc2-c2ccncc2)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2c(-c3ccncc3)cnn2-c2ccccc2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
3-(1-Phenyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (as regioisomeric mixture) was dissolved in dry dichloromethane (1 mL) under nitrogen atmosphere, 4-chloro-3-trifluoromethylphenylisocyanate (61 mg, 0.275 mmol, 1.4 eq) was added and the reaction mixture was stirred at room temperature for 3 hours. The solution was concentrated to dryness and purified by chromatography on silica gel (SP1, gradient n-hexane/ethyl acetate 1:1 to pure ethyl acetate). Two pools of fractions containing the two separated regioisomers were obtained, together with some mixed fractions (total yield 78%). 55 mg of 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(2-phenyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-urea were obtained as colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl>CN1CCCC1=O>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1cccc(C)c1CCl
Reactant: COC(=O)c1cnc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc2ccn(Cc3c(C)cccc3C)c2c1
Yield: 25.1 %

Procedure:
To a solution of methyl 1H-pyrrolo[3,2-b]pyridin-6-carboxylate (50 mg) in N-methyl-2-pyrrolidone (1 mL) were added potassium carbonate (158 mg) and 2,6-dimethylbenzyl chloride (91 mg), and then the reaction mixture was subjected to microwave irradiation at 160° C. for 30 minutes. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (21 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2C)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[CH:21]=[CH:22][S:48][C:25]=3[CH2:24][CH2:23][C@@H:19]2[CH3:20])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@@H]1C

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.51, 7.33, 7.11; 6.96, 5.66, 4.52, 2.95-2.62, 2.55, 2.38, 2.05, 1.97, 1.79, 1.26, 1.20, 1.07; HRMS (FAB) calcd for C23H25Cl2N3S+H 446.1224, found 446.1224.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1N.[CH3:10][S:11]SC.N(OC(C)(C)C)=O>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[S:11][CH3:10]
Reactant: Nc1cc(Cl)ccc1Br
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CSc1cc(Cl)ccc1Br
Temperature: 60 °C
Yield: 66.3 %

Procedure:
2-Bromo-5-chloroaniline (85.2 g, 0.41 mol) was dissolved in 1 L of acetonitrile followed by the addition of dimethydisulfide (30.0 mL, 0.33 mol). The flask was immersed in a water bath warmed to 60° C., equipped with a reflux condenser, and tert-butyl nitrite (54.0, 0.45 mol) was added in portions over 15 minutes. Once the addition was complete, the reaction was refluxed for 2 hours. After cooling to room temperature, the acetonitrile was evaporated, followed by re-dissolving in dichloromethane and subsequent concentration to remove remaining acetonitrile. The residue was re-dissolved in a minimal amount of dichloromethane and diluted with hexanes until precipitation was initiated. The mixture was filtered through a plug of silica and washed with hexanes. The filtrate was then concentrated in vacuo and crystallized upon cooling. 1-Bromo-4-chloro-2-methylsulfanylbenzene (52.0 g, 53%) was isolated via suction filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:39])[C:9]2[C:13]([CH2:14][N:15]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])C(=O)OC(C)(C)C)=[CH:12][N:11]([CH2:36][O:37][CH3:38])[N:10]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:39])[C:9]2[C:13]([CH2:14][NH:15][S:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)(=[O:24])=[O:25])=[CH:12][N:11]([CH2:36][O:37][CH3:38])[N:10]=2)=[CH:4][CH:3]=1
Reactant: COCn1cc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(C(O)c2ccc(F)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCn1cc(CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(C(O)c2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 33.5 %

Procedure:
tert-Butyl (3-((4-fluorophenyl)(hydroxy)methyl)-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl(4-(trifluoromethyl)phenylsulfonyl)carbamate (44) (434 mg, 0.757 mmol) was dissolved in CH2Cl2 (4 mL) and stirred at rt under nitrogen. Trifluoroacetic acid (4 mL) was added and the reaction stirred for 1 hr before concentration in vacuo. The resulting crude product was purified by column chromatography using EtOAc/hexane gradients to yield N-((3-((4-fluorophenyl)(hydroxy)methyl)-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl)-4-(trifluoromethyl)benzenesulfonamide (45) (120 mg, 35%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:18]=[CH:17][C:16]([N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)=[CH:21][CH:20]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-n3cncn3)cc2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (0.17 mL, 1.6 mmol), 4-{[1,2,4]triazol-1-yl}phenol (0.26 g, 1.58 mmol), and potassium carbonate (1.69 g, 12.2 mmol) in DMF was refluxed overnight. The reaction was cooled to room temperature, then partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with an aqueous sodium hydroxide solution (2N), water (2 times), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a yellow solid. Purification by column chromatography (silica gel; 1:1 hexane/ethyl acetate) and recrystallization from chloroform/hexane afforded 165 mg (37%) of the title compound as a yellow solid, mp 131-132° C. 1H-NMR (CDCl3): δ 8.55 (s, 1H), 8.25 (d, J=9 Hz, 2H), 8.12 (s, 1H), 7.75 (d, J=9 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29].C(OCC)C>C(Cl)Cl>[ClH:29].[F:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH:14]=[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(F)cc3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1

Procedure:
4-[3-(4-Fluoro-phenoxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 2.74 mmol) (Step 2) was dissolved in CH2Cl2 (20 mL) and treated with HCl in diethyl ether (8.2 mL, 16.4 mmol). After 16 hours the solution was concentrated and the residue suspended in diethyl ether. The resulting solid was filtered to provide the title compound as the hydrochloride salt (774 mg).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C=O)C>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][S:29]([CH3:28])(=[O:31])=[O:30])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 25 °C

Procedure:
To a solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (92 uL, 1.2 mmol) and triethylamine (0.2 mL, 1.5 mmol). The reaction mixture was stirred at 60C for 1 h, at 110° C. for 16 h, allowed to cool to room temperature and partitioned between EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography (1:1 of EtOAc/hexanes) provided the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 467 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1.[F:27][C:28]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]2[C:29]=1[CH:30](O)[CH2:31][CH2:32][O:33]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]2[C:29]=1[CH:30]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=4)(=[O:14])=[O:13])[C:6]=3[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1)[CH2:31][CH2:32][O:33]2
Reactant: OC1CCOc2cc(F)cc(F)c21
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O)cc(C(=O)N(C)C)cc32)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OC4CCOc5cc(F)cc(F)c54)cc(C(=O)N(C)C)cc32)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of 4-hydroxy-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide (110 mg, 0.294 mmol, STEP 7), 5,7-difluoro-3,4-dihydro-2H-chromen-4-ol (164 mg, 0.884 mmol, STEP 8-1) and triphenylphosphine (232 mg, 0.884 mmol) in toluene (5 mL) was added diisopropyl azodicarboxylate (DIAD) (179 mg, 0.884 mmol) at room temperature. The reaction mixture was stirred at room temperature for 6 hours and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane gradient elution from 1:20 to 10:1) to afford a mixture of the title compound and triphenylphosphine oxide (280 mg, crude) as white solids, which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=32)[CH2:3]1.[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>O1CCCC1.O>[CH3:23][O:1][CH:2]1[CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=32)[CH2:3]1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccc2c(c1)nc1n2CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1Cc2nc3cc([N+](=O)[O-])ccc3n2C1
Yield: 23.4 %

Procedure:
A solution of 0.28 g (1.28 mmol) of 2,3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole (step IX-2 of Example IX) in 5 ml of tetrahydrofuran is added to a suspension, stirred under argon at 20° C., of 0.2 g (5 mmol) of sodium hydride at 60% in 10 ml of tetrahydrofuran. After stirring for fifteen minutes, 0.24 ml (2.5 mmol) of dimethyl sulphate is added. The reaction mixture is stirred at 20° C. for 12 hours and then poured in 100 ml of water and extracted three times with 50 ml of ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 70 mg of the expected product are thus isolated in the form of a foam.