Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:11]([CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]2[CH2:22][CH:23]([CH3:25])[CH3:24])(=O)=O.[C-:37]#[N:38].[Na+]>CN(C)C=O>[CH3:20][N:16]1[C:17](=[O:19])[C:18]2=[C:10]([S:9][CH2:8][CH2:7][CH2:6][C:37]#[N:38])[N:11]([CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:12]=[C:13]2[N:14]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:15]1=[O:21]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCOS(C)(=O)=O)n(Cc3cccc4ccccc34)cc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC#N)n(Cc3cccc4ccccc34)cc21
Yield: 27.9 %

Procedure:
5-[(3-{Methanesulphonyloxy}propyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (391 mg) was dissolved in dimethyformamide (15 ml) and sodium cyanide (254 mg) was added. The mixture was sonicated for 4 hours and then poured onto sodium bicarbonate (aqueous). The mixture was extracted thrice with ethyl acetate, the extracts were combined, washed twice with water and once with brine, then dried, filtered and evaporated. The resultant oil was chromatographed, eluting with ethyl acetate : isohexane (4:5) and then triturated with cyclohexane-ethyl acetate to give the title compound (95 mg).
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].C(=O)([O-])[O-].[NH4+].[NH4+].C[N:20](C=O)C.CCN(CC)CC>O>[Br:1][C:2]1[C:3]([F:12])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:20]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
Prepared according to WO 2010/046388. 2-Bromo-1,3-difluoro-4-nitrobenzene (600a) (27.15 g, 114 mmol) was treated with ammonium carbonate (Sigma Aldrich, 10.96 g, 114 mmol) and DMF (200 mL) followed by Et3N (47.7 mL, 342 mmol) and stirred at RT for 48 h. The mixture was treated with water and extracted with DCM (300 mL). The DCM layer was washed with water (3×200 mL) and brine (3×200 mL), dried over MgSO4, filtered and concentrated affording crude 2-bromo-3-fluoro-6-nitroaniline (25.99 g, 111 mmol, 97% yield) as a bright yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (1H, dd, J=9.6, 5.9 Hz), 6.81 (2H, br. s.), 6.56 (2H, dd, J=9.6, 7.2 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −90.92 (1F, s). m/z (ESI, +ve ion) 234.9/236.9 (M+H)+.
Reaction SMILES: [OH-].[Ca+2].[OH-].[CH2:4]([O:7][C:8]([N:10]1[CH2:14][C@H:13](OS(C)(=O)=O)[CH2:12][C@H:11]1[CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:9])[CH:5]=[CH2:6].[C:26]([SH:29])(=[O:28])[CH3:27]>CC(C)CC(=O)C>[C:26]([S:29][C@@H:13]1[CH2:14][N:10]([C:8]([O:7][CH2:4][CH:5]=[CH2:6])=[O:9])[C@H:11]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH2:12]1)(=[O:28])[CH3:27]
Reactant: CC(=O)S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccnc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cn1ccnc1
Temperature: 82.5 °C

Procedure:
To a solution of calcium hydroxide (2.25 g) and (2S,4R)-1-allyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (10 g) in 4-methyl-2-pentanone (60 ml) was added dropwise thioacetic S-acid (4.38 ml) with stirring below 45° C. The solvent (18 ml) of the mixture was removed under reduced pressure at 40-45° C. The resulting suspension was heated at 80-85° C. for 2 hours. After cooling, water (20 ml) and ethyl acetate (20 ml) was added to the reaction mixture. The insoluble material was filtered off and washed with ethyl acetate (30 ml). The filtrate and washing were combined. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(imidazol-1-yl)methylpyrrolidine (7.94 g).
Reaction SMILES: C1COCC1.C[Si]([C:10]#[C:11][C:12]1[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:11]([C:12]1[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=1)#[CH:10]
Reactant: C[Si](C)(C)C#Cc1cccnc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccnc1N
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 62.8 %

Procedure:
To a THF (120 mL) solution of 3-trimethylsilanylethynyl-pyridin-2-ylamine (5.9 g) described in Manufacturing Example 1-1 was added tetrabutylammonium fluoride (34 mL: 1M THF solution) at 0° C., which was stirred for 25 minutes at room temperature. Water was added at 0° C. to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, and filtered, after which the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (2.3 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17](CC)[C:18](O)=O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:23]([O-:26])(=O)[CH3:24].[Na+].C(OC(=O)C)(=O)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:17][CH2:18][CH2:24][C:23]3=[O:26])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)[O-]
Reactant: CCC(NS(=O)(=O)c1ccc(N2CCOCC2)cc1)C(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCN1S(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
6.2 g of product obtained in Stage A, 6.2 g of sodium acetate and 124 cm3 of acetic anhydride are heated to reflux for 4 hours. After cooling to ambient temperature and evaporating to dryness, the residue is taken up with 50 cm3 of water, filtered, washed with 10 cm3 of water and dried. 5.65 g of expected product is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.N#N.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[C:27]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[C:26]([CH3:34])[N:25]([CH2:35][CH3:36])[C:24]2[CH2:37][O:38][C:39](=[O:40])[C:23]1=2.BrBr.C1CCCCC=1.C1C[O:52]CC1>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[C:27]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[C:26]([CH3:34])[N:25]([CH2:35][CH3:36])[C:24]2[CH:37]([OH:52])[O:38][C:39](=[O:40])[C:23]1=2
Reactant: C1CCOC1
Reactant: CCN1C(C)=C(C(=O)OC(C)C)C(c2ccccc2Cl)C2=C1COC2=O
Agent: BrBr
Agent: N#N
Agent: [Li]CCCC
Solvent: C1=CCCCC1
Solvent: CC(C)NC(C)C
Product: CCN1C(C)=C(C(=O)OC(C)C)C(c2ccccc2Cl)C2=C1C(O)OC2=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
60 mmol of diisopropylamine in 100 ml of analytical grade tetrahydrofuran are initially taken. 50 mmol of butyllithium are added at a temperature of 0°C., under a stream of N2. Thereafter, the mixture is cooled to -78° C. and a solution of 50 mmol of isopropyl 4-(2-chlorophenyl)-1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine3-carboxylate (dissolved in THF) is added dropwise. The mixture is stirred for 15 minutes at -78° C., and this solution is pumped, with the aid of nitrogen, into a solution of 50 mmol of Br2 and 50 ml of THF, and immediately thereafter 50 mmol of cyclohexene are added and the mixture is allowed to warm up to room temperature and is evaporated down, the residue is dissolved in DMSO, and H2O is added until the mixture starts to become cloudy. The mixture is left to stand for 12 hours, and the product is precipitated with H2O, filtered off under suction and separated with 9:1 CHCl3 /MeOH over silica gel.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.[Mg].II.Cl[P:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([CH3:31])([CH3:30])[CH3:29]>[Cu](Cl)Cl.C(OCC)C.CCCCCCC.C1COCC1>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: CC(Br)=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Agent: Cl[Cu]Cl
Agent: II
Agent: [Mg]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1)P(C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Yield: 20 %

Procedure:
Into a reactor were introduced 1.44 g (4.00 mmol) of the 1,1-bis(4-dimethylaminophenyl)-2-bromopropene obtained in Example 4 (2), 0.107 g (4.4 mmol) of magnesium, and 11.5 mL of THF under a nitrogen atmosphere. A slight amount of iodine was added to the mixture to ascertain initiation of a reaction. Thereafter, the reaction mixture was refluxed for 2 hours and then cooled. Thereto were added 0.416 g (4.2 mmol) of copper chloride and 0.91 mL (4.4 mmol) of chlorodi-tert-butylphosphine. The reaction mixture was refluxed for 18 hours and then cooled to room temperature. Thereto were added 22.5 mL of heptane and 7.5 mL of diethyl ether. The crystals yielded were taken out by filtration and dissolved in 30 mL of ethyl acetate. The resultant solution was washed with 28% ammonia water and an aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 0.34 g (20%) of the target compound as white crystals.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:40]=[CH:41][C:42]2[O:46][C:45](=[O:47])[N:44]([CH3:48])[C:43]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][C:45](=[O:47])[N:44]([CH3:48])[C:43]=3[CH:49]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 75 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 224 mg) in acetonitrile (10 mL) under nitrogen was treated with 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (99 mg) followed by an aqueous solution of potassium carbonate (2M, 0.433 mL) and 1,1 bis(bi-tert-butylphosphino)ferrocene palladium dichloride (6 mg). The reaction mixture was stirred at 75° C. for 18 h and then evaporated to an oil, dissolved in dichloromethane and absorbed onto silica. Purification by chromatography on silica eluting with 50% ethyl acetate in isohexane and then 100% ethyl acetate afforded the sub-titled compound (150 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])(O)=O.[Na+]>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.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:27]3[CH:28]=[C:23]([CH2:22][OH:21])[CH:24]=[CH:25][CH:26]=3)=[CH:10][C:3]=12
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1c(-c2cccc(CO)c2)cc2c(Br)ccnc21
Yield: 66 %

Procedure:
The above reaction was repeated two more times with 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (15 g of a reported 90% pure lot from CiVenti, 29.1 mMol) and 3-(hydroxymethyl)benzeneboronic acid (4.0 g, 26.3 mMol the first time, then 3.7 g, 24.3 mMol the second time). In both reactions dioxane (300 mL), aq. sat. NaHCO3 (75 mL), and (1.0 g, 0.86 mMol) of Pd(PPh3)4 was used. The amount of a bis-coupled side product was reduced from 26% to 15% and 13% respectively (by LCMS) in each of the reactions. All three reaction products (derived from a total of 40 g of 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine, 90% pure lot from CiVenti=36 g, 77.7 mMol) were combined and purified by flash chromatography by silica gel (10 to 15% EtOAc/CH2Cl2) to give the title compound (22.77 g, 66%) as a white solid: MS (ES) m/e 443.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=5.1 Hz, 1H), 7.85-7.91 (m, 2H), 7.70 (t, J=7.5 Hz, 1H), 7.63 (d, J=5.3 Hz, 1H), 7.59 (app. t, J=7.8 Hz, 2H), 7.53 (s, 1H), 7.44-7.50 (m, 3H), 6.75 (s, 1H), 5.35 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H).
Reaction SMILES: [Na].[F:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][CH:4]=1.[CH2:10]([P:12](Cl)(Cl)=[S:13])[CH3:11]>Cl[Hg]Cl.C(#N)C>[CH2:10]([P:12](=[S:13])([O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([F:2])[N:8]=1)[O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([F:2])[N:8]=1)[CH3:11]
Reactant: Oc1cccc(F)n1
Reactant: CCP(=S)(Cl)Cl
Agent: Cl[Hg]Cl
Agent: [Na]
Solvent: CC#N
Product: CCP(=S)(Oc1cccc(F)n1)Oc1cccc(F)n1
Reaction time: 5 h
Yield: 60 %

Procedure:
Into a 500 milliliter (ml) flask were placed 22 grams (g) (0.15 mole (m)) of the sodium salt of 6-fluoro-2-pyridinol, 1 gram HgCl2 and 200 milliliters of acetonitrile. The mixture was stirred while 9.5 grams (0.075 mole) of ethylphosphonothioic dichloride was added. An exotherm from 24° C. to 38° C. was obtained. The mixture was stirred at 40°-45° C. for five hours and allowed to cool. The insolubles were filtered off and the liquid phase distilled under reduced pressure until all the solvent was removed. The resulting oil was taken up in 300 milliliters of methylene chloride and washed once with 200 milliliters of water, once with 200 milliliters of aqueous 2% NaOH and twice with 200 milliliters portions of water. The product layer was dried over sodium sulfate, filtered and distilled under reduced pressure at 45° C. until the solvent was removed. The resulting oil was mixed in 150 mls of n-hexane and cooled to dry ice/acetone bath temperatures. The resulting solids were filtered off and dried to give a 60% yield of O,O-bis(6-fluoro-2-pyridinyl) ethylphosphonothioate, a solid, m.p. 47°-49° C. Product was confirmed by N.M.R. and I.R. spectra (compound No. 1).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)C.C[O-].[Na+].CI>C1COCC1.CO>[CH3:1][S:4][CH2:5][C:6]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc(CSC(C)=O)cc(C(=O)OCC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1cc(CSC)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To diethyl 5-(acetylthiomethyl)isophthalate (1.02 gm, 3.30 mmol) in THF (10 ml) and MeOH (10 ml), sodium methoxide (207 mg, 3.63 mmol) was added and stirred at rt for 2 h. Then methyl iodide (0.69 ml, 10.9 mmol) were added in two portions. After stirring at rt for 4 h, THF and MeOH were removed in vacuum and the reaction mixture was diluted with ethyl acetate. Organic layer was washed with water, brine and dried. Column purification of the crude residue yielded diethyl 5-(methylthiomethyl)isophthalate in 55% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][NH:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.CN(C(ON1N=NC2[CH:35]=[CH:36][CH:37]=[N:38]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>C1COCC1>[CH:37]1([NH:38][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([N:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([NH:4][CH2:3][CH:2]([CH3:23])[CH3:1])[C:13]=4[N:12]=[CH:11]3)=[CH:22][CH:21]=2)[CH2:35][CH2:36]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)CNc1cccc2c1ncn2-c1ccc(C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CNc1cccc2c1ncn2-c1ccc(C(=O)NC2CC2)cc1
Reaction time: 4 h
Yield: 34.4 %

Procedure:
To a stirred solution of 4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzoic acid (63 mg, 0.2 mmol) which was prepared according to intermediate example 4-1 in THF (5 mL), at rt was added HATU (85 mg, 0.22 mmol), DIPEA (29 mg, 0.22 mmol) and cyclopropylamine (12.8 mg, 0.22 mg) in one portion. After stirring for 4 h, the solution was evaporated and the remaining solid was purified by flash chromatography to yield N-cyclopropyl-4-{4-[(2-methylpropyl)amino]-1H-benzimidazol-1-yl}benzamide as an off-white solid (24 mg, 33.8%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: CC1c2ccc(OCCCBr)cc2C1CN1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1c2ccc(OCCCN=[N+]=[N-])cc2C1CN1CCCCC1

Procedure:
Sodium azide (1.49 g) is added to a stirred solution of 5-(3-bromopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene (7.3 g) dissolved in a mixture of ethanol/water (7.3 ml/73 ml). The reaction mixture is refluxed overnight, poured into water and extracted with ether. The organic extract is washed with sat'd aqueous NaCl, dried, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[C:7](=[O:9])[CH:8]=1.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[Cl-:1].[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:10]2[N:6]3[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][P+:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:4]=[C:5]3[S:12][CH:11]=2)[CH:14]=1
Reactant: O=c1cc(CCl)nc2scc(-c3cccnc3)n12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2scc(-c3cccnc3)n12
Product: [Cl-]
Reaction time: 40 h

Procedure:
7-chloromethyl-3-(3-pyridyl)-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 280°-290° C. dec. (5.30 g), prepared according to Example 6, was reacted with triphenylphosphine (5 g) in acetonitrile (500 ml) under stirring at the reflux temperature for 40 hours. After cooling the solution was concentrated in vacuo to a small volume, diluted with isopropyl ether and the precipitate was filtered to give 8 g of [3-(3-pyridyl)-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl]methyl-triphenylphosphonium chloride, which was suspended in dimethylsulfoxide (100 ml) and treated with potassium tert-butoxide (1.66 g) dissolved in dimethylsulfoxide (50 ml) under stirring at room temperature. The solution of the ylide so obtained was reacted with 3-pyridine-carboxaldehyde (1.74 g) at room temperature for 30 minutes then the reaction mixture was diluted with ice water and neutralized with NaH2PO4.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([CH2:13][NH2:14])[OH:12]>O1CCCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:14][CH2:13][CH2:11][OH:12]
Reactant: Clc1nc2ccccc2o1
Reactant: NCCO
Solvent: C1CCOC1
Product: OCCNc1nc2ccccc2o1

Procedure:
A solution of 2-chlorobenzoxazole (12.78 g) in dry tetrahydrofuran (50 ml) was added, over 10 minutes, to a stirred, ice-cooled solution of ethanolamine (15.3 g) in dry tetrahydrofuran (400 ml). The mixture was heated at reflux overnight, cooled, and the solvent evaporated. The residue was partitioned between water (500 ml) and dichloromethane (500 ml), and the resulting white solid filtered off, washed with dichloromethane and dried in vacuo to afford the title compound m.p. 162-4° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.C1C(O)=CC=C(O)C=1.OP(O)(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:7]=1
Reactant: CC(C)(O)c1cc(Br)ccc1F
Agent: O=P(O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Product: C=C(C)c1cc(Br)ccc1F
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (119.7 g, 498 mmol) in CH2Cl2 (50 ml) was added hydrochinone (2.74 g, 24.9 mmol) and 250 ml 85% H3PO4. The resulting reaction mixture was stirred for 3.5 h at 50° C. The mixture was poured onto ice-water and extracted with CH2Cl2. The organic phases were washed with 2N aqueous NaOH and water, dried over MgSO4, filtered and concentrated. The crude product was dissolved in hexane and filtered through a plough of silica gel to obtain after concentration at 600 mbar the title compound as a colorless oil: TLC (hexane): Rf=0.52; HPLC RtH5=1.416 min; 1H NMR (360 MHz, CDCl3): δ 7.43 (dd, 1H), 7.37 (m, 1H), 6.94 (dd, 1H), 5.27 (d, 2H), 2.13 (s, 3H).
Reaction SMILES: [OH-:1].[Na+].O.Br[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=1.[CH2:15]([Cl:17])Cl>>[Cl:17][C:15]1[C:9]([CH3:8])=[CH:10][C:5]([O:1][C:5]2[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=2)=[CH:6][C:7]=1[CH3:14]
Reactant: [OH-]
Reactant: ClCCl
Reactant: COc1c(C)cc(Br)cc1C
Agent: [Na+]
Solvent: O
Product: COc1c(C)cc(Oc2cc(C)c(Cl)c(C)c2)cc1C
Reaction time: 4.5 h

Procedure:
A mixture of 94 g of 4-chloro-3,5-dimethyl-phenol, 129 g of 4-bromo-2,6-dimethyl-anisole, 40 g of potassium hydroxide and 5 g of copper powder was slowly heated to 180°-190° C. During this operation, first the corresponding potassium phenolate formed, and the water formed separated by distillation with a small amount of 4-bromo-2,6-dimethylanisole. At about 200°-220° C., further reaction yielding phenoxy-anisole took place. After about 4 to 5 hours, the reaction was complete. The cooled substance was extracted to exhaustion with a solvent which is not miscible with water, such as methylene chloride. The filtrate of inorganic salts formed was then shaken several times with 2 N sodium hydroxide solution and water. After vaporization of methylene chloride a crude product was obtained which was still contaminated by 4-bromo-2,6-dimethyl-anisole. After distillation, 86 g of 4(4-chloro-3,5-dimethyl-phenoxy)-2,6-dimethyl-anisole were obtained, boiling point: 186° C. under a pressure of 3 mm mercury.