Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[C:11](I)[CH:10]=[CH:9][N:8]=1.[B:14](OCCCC)([O:20]CCCC)[O:15]CCCC.[OH-].[Na+]>C(OCC)C.O>[F:6][C:7]1[CH:12]=[C:11]([B:14]([OH:20])[OH:15])[CH:10]=[CH:9][N:8]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Fc1cc(I)ccn1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: OB(O)c1ccnc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of n-butyl lithium (3.2 mL, 2.5M, 8.0 mmol) in dry diethyl ether (20 mL) at −78° C. was added a solution of 2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and the reaction mixture was stirred at −78° C. for 10 min. Tributyl borate (2.4 mL, 2.01 g, 8.7 mmol) was added and the reaction mixture was allowed to stir to room temperature over 2 h. Water (5 mL) was added followed by 2N aqueous sodium hydroxide solution (10 mL) to dissolve the solids. The organic phase was separated. The aqueous phase was acidified to pH 3 using 6N HCl and the resulting white solid was collected by filtration and dried under vacuum to give the title compound, 0.74 g (78%). 1H NMR (d6 DMSO) δ 8.65 (br s, 2H), 8.21 (d, 1H, J=4.8 Hz), 7.59 (t, 1H, J=4.8 Hz), 7.37 (d, 1H, J=1.8 Hz).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[S:34][C:35]([CH3:38])=[CH:36][N:37]=3)=[CH:29][CH:28]=2)[NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:19])=[O:18])[N:10]=1)(C)(C)C.[OH-].[Na+]>O>[CH3:38][C:35]1[S:34][C:33]([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][CH:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:18])=[O:19])[C:11]3[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:14]=[CH:13][CH:12]=3)=[CH:32][CH:31]=2)=[N:37][CH:36]=1
Reactant: Cc1cnc(-c2ccc(CC(NS(=O)(=O)c3ccccn3)c3cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n3)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(-c2ccc(CC(NS(=O)(=O)c3ccccn3)c3cccc(NCC(=O)O)n3)cc2)s1
Yield: 54.9 %

Procedure:
Reaction was carried out in the same manner as in Example 19-(b) except for using tert-butyl[tert-butoxycarbonyl(6-{[4-(5-methylthiazol-2-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate (269 mg, 0.404 mmol) obtained in Example 22-(c) in place of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyridin-2-yl)benzyl]-(pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate. After completion of the reaction, water (20 ml) was added to the reaction solution, then it was adjusted to pH 10.9 with a 1N aqueous sodium hydroxide solution, and subsequently insolubles were filtered off. The filtrate was adjusted to pH 5.6 with 1N hydrochloric acid, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the resulting residue were added tert-butyl methylether (1 ml) and diisopropyl ether (10 ml), followed by sonication. A precipitated solid was collected by filtration, and then dried under reduced pressure to afford the title compound (113 mg) as a white solid. (Yield: 55%)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[C:44]([OH:46])[N:43]=[C:42]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)[CH:41]=2)[CH:37]=[N:38][CH:39]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:46][C:44]1[N:43]=[C:42]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[CH:41]=[C:40]([C:36]2[CH:37]=[N:38][CH:39]=[C:34]([C:15]3[CH:14]=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]4)=[O:11])=[CH:17][CH:16]=3)[CH:35]=2)[CH:45]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1cccc(-c2cc(-c3cncc(Br)c3)cc(O)n2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cccc(-c2cc(-c3cncc(-c4ccc(C(=O)N5CCN(C(C)C)CC5)cc4)c3)cc(O)n2)n1

Procedure:
To a solution of (4-Isopropyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (Intermediate B4) (1.1 eq, 0.161 mmol, 57 mg) and 2M Na2CO3 (2.0 eq, 0.292 mmol, 0.15 ml) in DME (1 ml) is added 5″-Bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-ol (Example 2.109; step1) (1 eq, 0.146 mmol, 50 mg) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.015 mmol, 12 mg). The reaction mixture is heated using microwave radiation at 90° C. for 90 mins. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 494
Reaction SMILES: I[CH:2]1[C:6]([CH3:8])([CH3:7])[C:5]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)[O:4][CH2:3]1.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.C1(C)C=CC=CC=1>>[CH3:7][C:6]1([CH3:8])[C:5]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)OCC(I)C2(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(C1)OCCC2(C)C
Temperature: 90 °C

Procedure:
A mixture of tert-butyl 3-iodo-4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (0.47 g, 0.0012 mol), tris(trimethylsilyl)silane (0.456 mL, 0.00148 mol) and 2,2′-azo-bis-isobutyronitrile (0.002 g, 0.00001 mol) in toluene (10.00 mL, 0.09388 mol) was heated at 90° C. overnight. The volatiles were removed in-vacuo and the residue was purified by CombiFlash, eluting with 0 to 30% EtOAc in hexane, to provide the THF compound. LCMS (M+Na) 278.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](C)([C:14]([O-])=O)[C:9]([O:11]CC)=[O:10])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.FC1C=C(C(C)(C(O)=O)C(O)=O)C=CC=1C1C=CC(F)=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1ccc(-c2ccc(F)cc2)c(F)c1
Agent: CC(C(=O)O)(C(=O)O)c1ccc(-c2ccc(F)cc2)c(F)c1
Product: CC(C(=O)O)c1ccc(-c2ccc(F)cc2)c(F)c1

Procedure:
By procedures similar to those described in Example 1, ethyl 2-(2,4'-difluoro-4-biphenylyl)-2-methylmalonate was hydrolysed and the resulting crude 2-(2,4'-difluoro-4-biphenylyl)-2-methylmalonic acid was decarboxylated to give 2-(2,4'-difluoro-4-biphenylyl)-propionic acid, m.p. 118°-119°C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)=[CH:33][C:32]=2[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=3)=[CH:33][C:32]=2[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncccn1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-pyrimidin-2-ylbenzenesulfonamide (Preparation 48) 356 mg, 0.47 mmol) was dissolved in 1,4-dioxane (1.5 mL) and a 4M solution of hydrogen chloride in 1,4-dioxane (2.4 mL) added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified by reverse phase preparative HPLC (Trilution method) to afford the title compound as a white solid (120 mg, 42%).
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.C[C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:10]1
Reactant: C[C@H]1CNCCN1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
Dissolve 2,3-dichloropyridine (7.4 g, 0.05 moles) and (S)-(−)-2-methylpiperazine (5.0 g, 0.05 moles) in DMA (125.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (20.75 g, 0.15 moles) to this mixture and stir at 135-140° C. for 56 hours. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3×200 mL) and wash the combined organic extract with brine (2×150 mL). Dry over MgSO4, and concentrate under vacuum to afford crude product as yellow liquid. Purify by flash column chromatography using CHCl3 to afford pyridylpiperazine derivative as yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][P:3](/[C:7](=[CH:12]/[O:13]C)/[C:8](OC)=O)([O:5][CH3:6])=[O:4].COP(/C(=C\OC)/C(OC)=O)(OC)=O.COC(=O)C(P(OC)(OC)=O)=COC.Cl.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][NH2:52])=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>COP(/C(=C\OC)/C(OC)=O)(OC)=O.CCOC(C)=O.CO>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[C:12]([OH:13])=[C:7]([P:3](=[O:4])([O:5][CH3:6])[O:2][CH3:1])[CH:8]=[N:52]2)=[CH:47][CH:46]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CO/C=C(\C(=O)OC)P(=O)(OC)OC
Agent: CO/C=C(/C(=O)OC)P(=O)(OC)OC
Agent: COC=C(C(=O)OC)P(=O)(OC)OC
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COP(=O)(OC)c1cnn(-c2ccc(Cl)cc2)c1O
Temperature: 45 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a slurry of methyl 3-oxy-2-dimethylphosphonoacrylate sodium salt (4.1 g, 0.017 mol) in anhydrous DMSO (25 mL) under nitrogen is added methyl iodide (4.5 g, 0.031 mol), and the reaction mixture stirred for 18 hours at ambient temperature. The mixture is poured into dilute sodium chloride solution and extracted with CH2Cl2 (6×75 mL). The extracts are washed with water (100 mL), dried (MgSO4), filtered and concentrated in vacuo to afford a brown oil (5.5 g). Partial separation by chromatography on silica gel (EtOAc) of half the crude product afforded pure E-isomer (0.27 g); a mixture of the E- and Z-isomers (0.75 g); and pure Z-isomer (0.14 g). The E- and Z-products are isolated in 52% overall yield. Methyl (E)-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (E-isomer). 1H NMR (300 MHz, CDCl3): δ 7.55 (d, JH-P=10.8 Hz, 1H), 4.06 (s, 3H), 3.78 (d, JH-P=2.7 Hz, 6H), 3.75 (s, 3H). 31P NMR (121 MHz, CDCl3) δ 20.74. Methyl (Z)-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (Z-isomer). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, JH-P=31.8 Hz, 1H), 4.03 (s, 3H), 3.78 (d, JH-P=5.1 Hz, 6H), 3.75 (s, 3H). 31P NMR (121 MHz, CDCl3) δ 15.50. A mixture of crude methyl-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate (6.9 g, 0.030 mol), 4-chlorophenylhydrazine hydrochloride (5.4 g, 0.030 mol), and methanol (40 mL) is heated and held at reflux under nitrogen for one hour. TLC (EtOAc) of an aliquot shows that the methyl-2-(dimethoxyphosphoryl)-3-methoxy-2-propenoate is consumed. After cooling to 45° C., water (15 mL) is added, followed by potassium carbonate (4.1 g, 0.030 mol). This mixture is heated and held at 65° C. for one hour. TLC of an aliquot shows complete conversion to product. The reaction mixture is cooled to 25° C., and further worked up as described for Method A, to afford compound 3a as a red-amber solid (5.90 g, 65%). 1H and 31P NMR spectra indicated 90% assay product, which results in a net 58% yield.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:9](F)=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=2[CH3:40])=[C:19]([CH3:41])[CH:18]=1.O>CS(C)=O>[Cl:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=3[CH3:40])=[C:19]([CH3:41])[CH:18]=2)=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: Fc1cnc(F)c(Cl)c1
Reactant: Cc1cc(O)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Oc2ncc(F)cc2Cl)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Cesium carbonate (476 mg, 1.46 mmol) was added to a mixture of 3-chloro-2,5-difluoropyridine (97%, 150 mg, 0.97 mmol) and C5 (366 mg, 0.972 mmol) in dimethyl sulfoxide (5 mL), and the reaction mixture was stirred at 80° C. for 6 hours. Water was added, and the mixture was extracted three times with ethyl acetate; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to 40% ethyl acetate in heptane) provided the product as a sticky solid. Yield: 414 mg, 0.818 mmol, 84%. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=2.7 Hz, 1H), 7.64 (dd, J=7.1, 2.7 Hz, 1H), 7.09-7.15 (m, 3H), 5.51 (AB quartet, JAB=9.3 Hz, ΔνAB=3.4 Hz, 2H), 3.74-3.80 (m, 2H), 3.07 (5, 3H), 2.19 (5, 3H), 1.69 (5, 3H), 1.00-1.06 (m, 2H), 0.03 (5, 9H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([O:5][CH2:6]1)[C:3](=[O:9])[O:2]2.O1C=CC[CH2:12][CH:11]1C([O-])=O.[Na+].C(I)C>CN(C)C=O>[O:5]1[CH:6]=[CH:1][CH2:8][CH2:7][CH:4]1[C:3]([O:2][CH2:11][CH3:12])=[O:9]
Reactant: O=C1OC2CCC1OC2
Reactant: O=C([O-])C1CCC=CO1
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC=CO1

Procedure:
The synthesis of 2,5-dioxabicyclo[2.2.2]octan-3 one was achieved through a three step reaction sequence as illustrated below: ##STR3## Sodium 3,4-dihydro-2H-Pyran-2-carboxylate was esterified with ethyl iodide in dimethylformamide to afford ethyl 3,4-dihydro-2H-pyran-2-carboxylate. Subsequent hydroboration with a borane solution in tetrahydropyran at 0° C., followed by oxidation with a sodium dichromate-sulfuric acid aqueous solution and subsequent treatment with sodium hydrogen sulfite gave ethyl 5-hydroxytetrahydropyran-2-carboxylate as a stereoisomer mixture. The hydroxytetrahydropyran ester was heated in a dilute solution in the presence of a catalytic amount of p-toluenesulfonic acid, any ethyl alcohol being liberated was removed through a Soxhlet extractor containing type 5A molecular sieves. Column chromatographic separation of the reaction products and subsequent repeated recrystallization gave the bicyclic lactone as colorless crystals; the overall yield was approximately 20%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Al](C)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH:26]([C:28]#[N:29])[N:25]=[C:24]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[CH:19][CH:18]=1.CO.O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH:26]([C:28]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])=[NH:29])[N:25]=[C:24]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])=[CH:21][CH:22]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#CC1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Agent: C[Al](C)C
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: N=C(NS(=O)(=O)c1ccc(Cl)cc1)C1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Part A: To a suspension of 4-chlorobenzenesulfonamide (0.45 gram, 0.00236 mol) in benzene (5 ml) is dropwise added trimethylaluminum (1.2 ml of a 2N solution in toluene, 0.0024 mol) to give a clear solution which is stirred at room temperature for 1 hour. 1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carbonitrile (0.55 gram, 0.00157 mol) is added and the resulting mixture is heated at 90° C. for 16 hours. After cooling to room temperature a mixture of methanol/water (8/2 (v/v)) is slowly added, the solids are removed by filtration and washed with chloroform (50 ml). The filtrate is concentrated in vacuo. The residue is triturated with n-pentane and twice recrystallised from methanol to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-1H-imidazole-4-carboxamidine (0.435 gram, 51% yield). Melting point: 165-166° C. 1H-NMR (200 MHz, CDCl3): δ 4.11-4.35 (m, 2H), 4.94 (dd, J=12 and 10 Hz, 1H), 6.63 (br d, J=8 Hz, 2H), 7.12 (br d, J=8 Hz, 2H), 7.22-7.52 (m, 6H), 7.90 (br d, J=8 Hz, 2H), 8.10-8.20 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([NH2:22])=[O:21].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([NH2:22])=[O:21])=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CN(CC(=O)N1CCC[C@H]1C(N)=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 64.7 %

Procedure:
Nα-(tert-Butyloxycarbonyl)-Nα-(2-methylpropyl) glycine (360 mg, 1.56 mmol) was dissolved in CH2Cl2/DMF (9:1, 20 ml). The solution was cooled to 0° C., L-prolinamide hydrochloride (282 mg, 1.87 mmol), 1-hydroxybenzotriazole hydrate (295 mg, 2.18 mmol) and water soluble carbodiimide (358 mg, 1.87 mmol) were added and after 15 min the pH adjusted to pH9 with triethylamine. After 18 h at 0° C. to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 4% methanol, 94% chloroform, 2% triethylamine) to give a colourless oil identified as the title compound (330 mg, 1.01 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl.Cl[CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1
Reactant: ClCc1cscn1
Reactant: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: Cl
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Yield: 17 %

Procedure:
The procedure described in Example 3 was repeated using N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described for in Example 50, preparation of starting materials) and 4-(chloromethyl)-thiazole hydrochloride to give the title compound in 17% yield; NMR spectrum (DMSO-d6) 1.36 (d, 3H), 1.94 (s, 3H), 3.02 (s, 3H), 3.3O (1H obscured by H2O), 4.21 (dd, 1H), 5.09 (m, 1H), 5.33 (s, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 7.81 (s, 1H), 8.08 (s, 1H), 8.47 (s, 1H), 9.13 (s, 1H), 9.96 (s, 1H); Mass Spectrum MH+ 498.
Reaction SMILES: C([O:3][P:4]([O:8]CC)[O:5]CC)C.[C:11]([BH2:15])([O:13][CH3:14])=[O:12].[Si:16](I)([CH3:19])([CH3:18])[CH3:17]>CC#N>[P:4]([O:8][Si:16]([CH3:19])([CH3:18])[CH3:17])([O:5][Si:16]([CH3:19])([CH3:18])[CH3:17])[O:3][Si:16]([CH3:19])([CH3:18])[CH3:17].[C:11]([BH2:15])([O:13][CH3:14])=[O:12]
Reactant: C[Si](C)(C)I
Reactant: CCOP(OCC)OCC
Agent: BC(=O)OC
Solvent: CC#N
Product: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
Triethylphosphite-carbomethoxyborane (4) (1.13 g, 4.75 mmol) and Me3SiI 2.70 ml, 18.97 mmol) were taken in anhydrous CH3CN (45 ml) under nitrogen atmosphere. Immediately, the mixture became brown. It was heated at reflux for 3 hours. During this time, the brown color completely disappeared, the mixture was cooled, and the solvent was removed under reduced pressure to give a yellow solid. 11B NMR (CDCl3) : ∂=15 ppm, br. s., 0.2 ppm, br. s., major and a multiplet at -39 ppm, very small amount.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10]C)[C:5]([O:8]C)=[CH:6][CH:7]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:6][CH:7]=1)[OH:8]
Reactant: COc1ccc(Br)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
6.51 g (0.0300 mol) of 4-bromoveratrole is dissolved in 50 ml of dichloromethane. To this suspension is added 37.6 g (0.150 mol) of boron tribromide at 0° C. The mixture was stirred for 3 hours at room temperature. Solvents were removed under reduced pressure. The resulting brown oil was dissolved in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated to afford 5.45 g of 4-bromo catechol as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
p-Chlorophenol (7 g), p-nitrobromobenzene (11.0 g) and potassium carbonate (9.02 g) in dimethylsufoxide (35 ml) were heated with stirring at 120° C. for 24 hours and cooled, and the mixture was poured into water. The resulting precipitate was collected by filtration and washed with water. The resultant was heated in a mixed solvent of methanol/water [4:1,(v/v)], and allowed to cool. The resulting product was collected by filtration to give 4-(4-chlorophenoxy)nitrobenzene (12.92 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([O:1][CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Oc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)COc1cccc(Cl)n1
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a stirred mixture of 400 g (3.09 moles) of 2-hydroxy-6-chloropyridine and 450 g (3.26 moles) potassium carbonate in 3000 ml acetonitrile was added 551 g (3.08 moles) 1-bromo-3,3-dimethyl-2-butanone. The reaction mixture was stirred at 45°-50° C. for 1.5 hours and then filtered. The solids were washed several times with acetonitrile, the filtrate dried (MgSO4) and the solvent evaporated. Crystallization of the residue from pentane gave 610 g (87% yield) of 1-(6-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone. A second recrystallization from pentane gave product melting at 43°-44.5° C.