Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH3:11][O:12][C:13](=[CH2:16])[C:14]#[N:15].[CH2:17]([N:24]([CH2:30]OC)[CH2:25][Si](C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH2:17]([N:24]1[CH2:25][CH2:16][C:13]([C:14]#[N:15])([O:12][CH3:11])[CH2:30]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C(C#N)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(C#N)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.2 g triflouroacetic acid and 1.2 g triethylamine in 200 ml dry dichloromethane 8.3 g (90 mmol, 90% proof) 2-methoxyacrylonitrile (J. Chem. Soc. 520, 1942) are added. Thereafter 28.5 g N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)-amine (Chem. Letters 1117, 1984) are added, and the mixture is stirred overnight at room temperature. The mixture is treated with a saturated solution of sodium hydrogencarbonate, dried with magnesiumsulfate, and finally the organic solvents are removed in vacuo and the residue is destilled.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[C:7]([O:9]C(C)(C)C)=O.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([O:16][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])[CH3:15])[CH2:7][OH:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(Cc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(CO)Cc1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Yield: 76.3 %

Procedure:
1.14 g of tert-butyl (2RS, 3RS)-2-(3,4-dichlorobenzyl)-3-hydroxybutanoate obtained in Example 123 was dissolved in 10 ml of dimethylformamide, and 0.65 g of tert-butyldimethylchlorosilane and 0.37 g of imidazole were added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl ether, then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of toluene, and then a 1M toluene solution of diisobutylaluminum hydride was added thereto with stirring under cooling to -78° C. The mixture was stirred at the same temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution with stirring under cooling to -78° C., and the temperature was raised to room temperature. Then, 1N hydrochloric acid and ethyl acetate were added thereto for liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.99 g (yield: 76%) of (2RS, 3RS)-2-(3,4-dichlorobenzyl)-3-(tert-butyldimethylsilyloxy)butanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)[CH:17]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:12]4[N:11]([CH3:27])[N:10]=[N:9][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=[CH:15]3)=[N:19][CH:20]=2)[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3CC3)cn2)cn1
Yield: 56 %

Procedure:
As described for example 22, 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (69 mg, 0.189 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (43 mg, 56%) which was obtained as a white foam. MS: m/e=404.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.Cl.Cl[C:11]1C=CC=NC=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][N:17]1[CH2:22][CH2:21][N:20]([C:5]2[N:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=2)[CH2:19][CH2:18]1
Reactant: Clc1cccnc1
Reactant: C1CNCCN1
Reactant: Nc1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN(c2ccc(N)nn2)CC1
Yield: 53.6 %

Procedure:
An amount of 1.0 g (7.72 mmol) of 3-amino-6-chloropyridazine, 5-chloro pyridine hydrogen chloride (4.46 g, 38.6 mmol), and piperazine (5.1 mL, 72 mmol) were placed in a pre-heated oil bath at 165-170° C. for 4 hours. After cooling, the mixture is basified with saturated potassium carbonate, extracted 3× with ethyl acetate and dried over magnesium sulfate. The oily residue is purified by column chromatography to give a brown solid 800 mg (53% yield). MS (ESI) m/z 194.3 (M+1)+
Reaction SMILES: [Cl:1]C1C=C(O)C(O)=CC=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([OH:19])=[O:18].[OH-:20].[Na+:21]>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([Cl:1])(=[O:19])=[O:18].[S:17]([O-:19])([O-:20])=[O:18].[Na+:21].[Na+:21]
Reactant: O=S(O)c1ccccc1Cl
Reactant: [OH-]
Reactant: Oc1ccc(Cl)cc1O
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccccc1Cl
Product: O=S([O-])[O-]

Procedure:
24.6 g (170 mmol) of 4-chloro-1,2-benzenediol are added while stirring, under nitrogen, to a solution of 28.8 g (163 mmol) of 2-chlorobenzenesulphinic acid (obtained by the reduction of 2-chlorobenzenesulphonyl chloride with sodium sulphite) in 163 ml of 1N sodium hydroxide solution. In the course of 40 minutes there is added dropwise thereto, at room temperature, a solution of 82 g (240 mmol) of potassium hexacyanoferrate (II) and 150 g of sodium acetate trihydrate in 300 ml of water. The solution becomes turbid and an oil forms which, after stirring for 2 hours, crystallises. The reaction mixture is extracted three times with ethyl acetate. The organic phases are washed with water and saturated sodium chloride solution, dried and concentrated by evaporation. The crude brown crystals are dissolved in warm isopropanol and treated with activated carbon. The solution is filtered, concentrated to 200 ml, added dropwise to 800 ml of ice-cold water and stirred for 2 hours while cooling with ice. The white suspension is filtered with suction, and the filtration residue is washed with water and dried, yielding 4-chloro-5-(2-chlorophenylsulphonyl)-1,2-benzenediol in the form of white crystals having a melting point of 226°-229°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[N:8]=1
Reactant: Nc1cccc(CCCO)c1
Reactant: COc1cc(Br)cc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Br)cc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 70 °C
Yield: 98.9 %

Procedure:
Into a reaction flask were added N-(3-bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine (2.0 g, 5.5 mmol), 1,4-dioxane (30 mL), 3-(3-aminophenyl)propan-1-ol (1.2 g, 8.3 mmol, prepared according to Example 12, Step B), and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol). The mixture was heated at 70° C. over two days and NaHCO3 (saturated aqueous solution) was added. After removal of the organic solvent, the aqueous layer was extracted with methylene chloride twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product as a white powder (2.6 g, 99%). LCMS for C21H22BrClN4O2 (M+H)+: m/z=477.0, 479.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16]>O1CCCC1.COC(C)(C)C.[Pd](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=[N+]([O-])c1ccccc1-c1cc(F)c(F)c(F)c1
Temperature: 105 °C

Procedure:
A well-inertized pressure vessel was initially charged with a mixture of 49.6 g (0.113 mol) of a 40% solution of 3,4,5-trifluorophenylboronic acid in tetrahydrofuran from preliminary stage a) with 121.6 g (0.304 mol) of a 10% sodium hydroxide solution and 19.7 g (0.124 mol) of 2-nitrochlorobenzene. The particular ligand was then added at room temperature, the mixture was stirred and the palladium(II) chloride was finally added. Subsequently, the reaction mixture was heated to 105° C. This established a pressure of approx. 3-4 bar. After about 12 hours of reaction time, the pressure vessel was decompressed to standard pressure and cooled to 30° C., and the reaction mixture was discharged. For workup, the reaction mixture was taken up in tert-butyl methyl ether, the phases were separated and the aqueous phase re-extracted twice with tert-butyl methyl ether. The solvents were distilled off completely under reduced pressure, the final weight was determined and the content of the crude 3,4,5-trifluoro-2′-nitrobiphenyl was analyzed by means of quantitative HPLC. If desired, the crude 3,4,5-trifluoro-2′-nitrobiphenyl can be purified further, for example by crystallization from isobutanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([NH:19][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:22][O:23][C:24]1[C:29]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH:17]([NH:19][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CC(NC=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1cccc(-n2cnc3cc(C(C)NC=O)ccc32)c1
Yield: 77 %

Procedure:
This was prepared analogously from N-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-formamide and 2-methoxypyridine-3-boronic acid in 77% yield. LC-ESI-HRMS of [M+H]+ shows 373.1666 Da. Calc. 373.166451 Da. dev. 0.4 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].C(Cl)Cl>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[N:18]\[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1cccc(Br)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a round-bottomed flask charged with 1-(3-bromophenyl)-2-fluoroethanone (11.42 g, 52.6 mmol) in THF (100 ml), was added (R)-2-methylpropane-2-sulfinamide (12.75 g, 105 mmol). Then tetraisopropoxytitanium (31.2 ml, 105 mmol) was added into the reaction mixture. The reaction mixture was stirred at ambient temperature under inert atmosphere overnight. The material was poured slowly into a vigourously stirring solution of ice water. The resulting suspension was stirred vigourously for 20 min. Then methylene chloride was added into the mixture and the overall mixture was allowed to stir an additional 30 min. The mixture was filtered through a pad of celite and the filter cake was washed with methylene chloride. The organic layer was separated and the remaining aqueous layer was extracted with methylene chloride three times. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in-vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column, eluting with a gradient of 0-15% EtOAc/hexane to give (R,E)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (9.69 g, 57.5% yield).
Reaction SMILES: [N:1]1([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[N:1]1([C:8]([CH3:12])([CH3:11])[CH:9]([NH2:10])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C#N)N1CCCCCC1
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: CC(C)(C(N)c1ccccc1)N1CCCCCC1
Yield: 83 %

Procedure:
The title compound (3.7 g; 83%) was prepared from 2-(hexahydro-1H-azepin-1-yl)-2-methylpropanenitrile D41 (3 g; 18 mmol) and phenyllithium in dibutylether (18 ml of a 2M solution; 36 mmol) in THF (100 ml), followed by reaction with sodium borohydride (2.13 g, 54 mmol) in methanol (100 ml) in a similar manner to that described in D5. 1H NMR (CDCl3) δ 0.78 (3H, s), 0.98 (3H, s), 1.55-1.70 (8H, m), 1.83 (2H, br s), 2.67-2.79 (4H, m), 4.18 (1H, s), 7.20-7.30 (3H, m), 7.40-7.42 (2H, m).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:5][C:6]#[N:7].[CH3:18]OS(OC)(=O)=O>C1COCC1.O>[CH3:18][O:3][CH:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:5][C:6]#[N:7]
Reactant: N#CCC(O)c1ccc2ccccc2c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CC#N)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a suspension of NaH (1.50 g, 37.5 mmol, 60% dispersion) in dry THF (200 mL) cooled to 0° C. was added 3-hydroxy-3-(2-naphthalenyl)propionitrile (4.92 g, 25 mmol) in THF (50 mL) dropwise over 20 minutes. The resulting solution was stirred at 0° C. for 5 minutes and dimethylsulfate (4.72 g, 37.5 mmol) was added in one portion. The reaction mixture was stirred at 0° C. for 20 minutes and room temperature for 1.5 hours. The reaction was then diluted with H2O (50 mL) and the volatiles were removed in vacuo. The residue was partitioned between CH2Cl2 (250 mL) and H2O (200 mL). The aqueous phase was extracted with CH2Cl2 (1×250 mL), the combined organic layers dried (Na2SO4) and concentrated in vacuo to give a thick yellow oil. This was purified by preparative HPLC (SiO2 : gradient EtOAc/hexane) to give the product as a light yellow oil (4.58 g, 87%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][CH2:32][C@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[C@@H:28]([OH:33])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCNC[C@H]1O
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)[C@@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4S*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f11) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:33](=[O:40])[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:17]2(=[O:32])=[O:31])=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:17]2(=[O:31])=[O:32])=[CH:14][CH:15]=1)[C:33]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:40]
Reactant: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCNC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1
Reaction time: 0.33 h

Procedure:
A solution of the title A compond, ((S)-2-(4-[5-{4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamic acid t-butyl ester (64 mg, 0.108 mmol) in CH2Cl2 (1 mL) is treated with TFA (1 mL). After 20 min, the solvent is evaporated under stream of nitrogen. The residue is partitioned between EtOAc and saturated aqueous NaHCO3, and the organic solution is washed with brine, dried over anhydrous MgSO4, filtered and concentrated to yield (S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide as a white solid: [M+1]+=489.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[C:21]([CH3:22])=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(O)(C)C>[CH3:12][C:13]1[C:21]([CH3:22])=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[C:2]2[C:3]3[CH:11]=[CH:10][N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncnc2cnccc12
Reactant: Cc1ccc2c(c1C)NCC2
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Cc1ccc2c(c1C)N(c1ncnc3cnccc13)CC2
Yield: 17.9 %

Procedure:
To 4-chloro-pyrido[3,4-d]pyrimidine (200 mg, 1.21 mmol) in isopropanol (3 mL) was added 6,7-dimethylindoline (211 mg, 1.44 mmol) and pyridine (190 mg, 2.41 mmol). The mixture was heated to reflux under an atmosphere of dry N2(g) for 6hours. Solvent was removed in vacuo and the residue was dissolved in CHCl3 and washed with saturated aqueous Na2CO3. The organic phase was dried over Na2SO4, concentrated in vacuo, and flash chromatographed on silica in 45% acetone/hexanes to afford 60 mg of 4-(6,7dimethyl-2,3-dihydro-indol-1-yl)-pyrido[3,4-d]pyrimidine (LC-MS: 278 (MH+). This material was dissolved in a minimum volume of 10% MeOH in CH2Cl2, and 1 mole equivalent of HCl in diethyl ether was added dropwise with stirring. The mixture was diluted with diethyl ether (4 volumes) and the precipitated HCl salt of the product was filtered and dried in vacuo (58 mg): MP: 248° C.; GEMS: 277 (M+); anal. RP-HPLC: 4.06 minutes.
Reaction SMILES: [C:1]1(=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=N)[NH:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=N)[NH:2]1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[CH2:23]1.[C:32]([OH:35])(=O)[CH3:33]>CN1C(=O)CCC1>[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[C:23]1=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[C:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[C:33]3[C:32](=[O:35])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]3=[O:21])[NH:2]2)[NH:12]1
Reactant: N=C1NC(=C2NC(=N)c3ccccc32)c2ccccc21
Reactant: O=C1CC(=O)c2ccccc21
Reactant: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C1C(=c2[nH]c(=c3[nH]c(=C4C(=O)c5ccccc5C4=O)c4ccccc34)c3ccccc23)C(=O)c2ccccc21
Temperature: 25 °C

Procedure:
10.0 g of [1,1′]biisoindolylidene-3,3′-diimine and 16.9 g of 1,3-dioxoindane are stirred in a mixture of 100 ml of NMP and 100 ml of glacial acetic acid at reflux for 6 hours. After cooling to room temperature the suspension is filtered, the filter product is washed with a mixture of NMP and glacial acetic acid (1:1), subsequently ethanol and then water and dried at 60° C. This gives 10.8 g (54%) of a black powder of a compound of the following formula
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[OH:20][C:21]1[CH:25]=[C:24]([N:26]2[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[S:23][C:22]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+].Br[CH:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54]([F:57])([F:56])[F:55])[CH3:47]>CN(C)C=O>[N:7]1([C:5]2[S:4][C:3]([C:16]([O:18][CH3:19])=[O:17])=[C:2]([O:1][CH:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[C:54]([F:55])([F:56])[F:57])[CH3:47])[CH:6]=2)[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:9]=[CH:8]1.[N:28]1[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[N:26]([C:24]2[S:23][C:22]([C:35]([O:37][CH3:38])=[O:36])=[C:21]([O:20][CH:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[C:54]([F:55])([F:56])[F:57])[CH3:47])[CH:25]=2)[CH:27]=1
Reactant: CC(Br)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OC(C)c1ccccc1C(F)(F)F
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OC(C)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 300 mg of an isomeric mixture of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate (example C1) and 181 mg K2CO3 and 332 mg 1-(1-bromoethyl)-2-(trifluoromethyl)benzene in ml N,N-dimethylformamide yield methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{1-[2-(trifluoro-methyl)phenyl]ethoxy}thiophene-2-carboxylate and methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][OH:6].[C:13](Cl)([Cl:15])=[O:14]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][O:6][C:13]([Cl:15])=[O:14]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(OC)c(CO)c1
Solvent: c1ccccc1
Product: COc1ccc(OC)c(COC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50% solution of 2,5-dimethoxybenzyl alcohol and dry benzene was added dropwise to an ice-cold stirring solution of 12.5 wt. % phosgene in benzene (1 mole of alcohol per 2 moles phosgene). The resulting solution was maintained at 0° for 1 hour and then stirred an additional 2 hours at room temperature. Excess phosgene, byproduct hydrogen chloride and a small amount of benzene was removed in vacuo at room temperature to provide crude 2,5-dimethoxybenzyloxycarbonyl chloride solution. The crude product was added dropwise to a 50 wt. % solution of p-aminobenzoic acid in dry tetrahydrofuran containing 2 moles of pyridine per mole of acid. An additional two equivalents of pyridine was added dropwise simultaneously with the carbonyl chloride addition. Upon completion of the addition (25-40 mins.), the resulting mixture was added dropwise with stirring to ice-cold 5% aqueous hydrochloric acid (10 volumes of acid per final volume of reaction solution). The product was collected by filtration, dried and purified by recrystallization from acetone. m.p. 124-25.