Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH3:14])=[O:10])[S:4][N:3]=1.[C:15]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([Sn](C)(C)C)=[CH:28][CH:29]=2)[CH:24]=[N:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[C:6]([Br:7])=[C:5]([NH:8][C:9]([C@@H:11]4[CH2:13][C@H:12]4[CH3:14])=[O:10])[S:4][N:3]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Reactant: CC(C)(C)OC(=O)n1ncc2cc([Sn](C)(C)C)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3c(cnn3C(=O)OC(C)(C)C)c2)c1Br
Temperature: 85 °C

Procedure:
Dissolve (1R,2R)-2-methyl-cyclopropanecarboxylic acid (3,4-dibromo-isothiazol-5-yl)-amide (3.0; g, 8.82; mmol) in anhydrous 1,4-dioxane (88; mL) and add 5-trimethylstannanyl-indazole-1-carboxylic acid tert-butyl ester (4. 11; g, 9.70; mmol). Blanket under nitrogen, add bis(triphenylphosphine)palladium(II) chloride (0.62; g, 0.88 mmol) and heat to 85° C. for 4; days. Concentrate and purify the residue by silica gel chromatography, gradient eluting from 20:80; to 40:60; ethyl acetate:hexanes to give the title compound (1.04; g, 70% purity wt/wt, 17%) which is carried on with out further purification. MS (m/z): 477, 479; (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.CCN(C(C)C)C(C)C.Cl[C:31]1[N:36]=[CH:35][N:34]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:32]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:31]4[N:36]=[CH:35][N:34]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:32]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N2CCC(N3CCc4cc(OC)ccc4NC3=O)CC2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.80 g (10.2 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 6.00 mL (34.9 mmol) DIPEA were added to 1.90 g (10.2 mmol) ethyl 6-chloropyrimidine-4-carboxylate in 60 mL DMF and the reaction mixture was stirred for 3 h at RT. After elimination of the solvent i. vac. the residue was combined with 70 mL water and stirred for 10 min. 5 mL ethyl acetate were added. After vigorous stirring the solid was suction filtered and dried in the CAD.
Reaction SMILES: N1C2=CC=C(N)CC2NC1.C([BH3-])#N.[Na+].[CH2:15]([O:22][C:23]1[CH:44]=[C:43]([Cl:45])[C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][N:30]([N:33]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:36]=4[N:35]=[CH:34]3)[C:29]2=[O:42])=[C:25]([Cl:46])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO.C(OCC)(=O)C>[CH2:15]([O:22][C:23]1[CH:44]=[C:43]([Cl:45])[C:26]([CH2:27][C@@H:28]2[CH2:32][CH2:31][N:30]([N:33]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:36]=4[N:35]=[CH:34]3)[C:29]2=[O:42])=[C:25]([Cl:46])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1n1cnc2c1CCCC2
Agent: NC1=CC=C2NCNC2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1n1cnc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add Preparation 10 (5.25 g) to a suspension of imidazolocyclohexy-3-amine hydrochloride (2 gm) (Preparation 8) in methanol (30 mL). Stir the mixture at room temperature for 30 min. Add sodium cyanoborohydride (1 g) and stir the mixture for 2 h. Heat the reaction mixture at 50° C. for 2 h. Dilute the reaction mixture with ethyl acetate (50 mL) and wash the mixture with water (50 mL). Dry ethyl acetate layer over sodium sulfate and concentrate on rotary evaporator to give a crude. Purify the crude by silica flash chromatography eluting with a gradient of 0-5% methanol in DCM to give the product as a mixture of diastereomers, 3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-3H-benzimidazole-3-yl)-pyrrolidin-2-one (4.5 gm). MS: m/z=470 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:17])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 6.97 g of oxalyl chloride at 5° C. to a mixture of 100 ml of THF and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 250 ml of ice water to precipitate crystals. The crystals were collected by filtration and washed with 100 ml of ice water. The resulting crystals were thereafter suspended in water and the suspension was adjusted to pH 4.0 with a 1M aqueous solution of sodium acetate. The resulting solution was extracted with 250 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, followed by filtration. The filtrate was concentrated and, under reduced pressure, was then dried, whereby the title compound was obtained. Yield: 7.5 g (68.7%). Purity: 98.7 %.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:17])([F:16])[C:6]1[CH:7]=[C:8]([CH2:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[CH3:14][C:13]([OH:15])([CH3:1])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]([F:16])([F:17])[F:4])[CH:7]=1
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)Cc1cccc(C(F)(F)F)c1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
90 mL of a 3 molar solution of methylmagnesium bromide in diethyl ether are diluted with 300 mL THF and cooled to −50° C. At this temperature 20 g 1-(3-trifluoromethyl-phenyl)-propan-2-one, dissolved in 100 mL THF, are added dropwise. After the addition has ended the reaction mixture is stirred overnight while heating to ambient temperature. It is combined with ammonium chloride solution and extracted with diethyl ether. The combined organic phases are washed with sodium chloride solution, dried with sodium sulphate and evaporated down. The residue remaining is purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11]([CH3:15])=[N:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:32]([O:31][C@@H:27]1[C@@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[O:29][C@H:28]1[O:16][C:9]1[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)=[C:13]([CH3:14])[N:12]=[C:11]([CH3:15])[N:10]=1)(=[O:33])[CH3:34]
Reactant: COc1ccc(Cc2c(C)nc(C)[nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cc2c(C)nc(C)nc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 34 %

Procedure:
To a solution of 5-(4-methoxybenzyl)-2,6-dimethyl-3H-pyrimidin-4-one (0.30 g) in acetonitrile (6 mL) were added acetobromo-α-D-glucose (0.76 g) and potassium carbonate (0.27 g), and the mixture was stirred for 17 hours at 60° C. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethyl acetate=1/1) and on silica gel (eluent: hexane/ethyl acetate=1/1-1/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-(4-methoxybenzyl)-2,6-dimethylpyrimidine (0.24 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:19])=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.ClCCl.O.C[N:33](C)C=O>>[NH2:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:19])=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2c(C)c3cc(OC)ccc3n2CCCCCCBr)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2c(C)c3cc(OC)ccc3n2CCCCCCN)cc1

Procedure:
8.0 mmol of 1-(6-bromohexyl)-5-methoxy-2-(4-methoxyphenyl)-3-methyl indole and 8.8 mmol of phthalamidepotassium are heated in 100 ml of anhydrous dimethylformamide for 2 hours under reflux. Following cooling the product is shaken with dichloromethane and H2O. The product is then dried over Na2SO4 and the solvent distilled off. The residue is chromatographed on silica gel with dichloromethane. To liberate the amine the so-obtained colorless crystals are taken up in 50 ml of ethanol (99%) and mixed with hydrazine hydrate in 20 ml of ethanol. The mixture is now heated for 2 hours under reflux; after cooling, it is acidified with 40 ml of 2N HCl solution and suctioned off from the precipitate. After distilling off the solvent the mixture is made alkaline with 40 ml of 2N NaOH and extracted three times with ethyl acetate. The mixture is then dried over Na2SO4 and chromatographed on silica gel with dichloromethane/ethyl acetate (10:1, volume/volume). A viscous colorless to yellowish oil is obtained.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:53][CH:52]([N:54](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:55]=[NH:56])[CH2:51]2)=[O:49])[CH2:43]1>>[CH:55]([NH:54][CH:52]1[CH2:51][N:50]([C:48]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][N:45]2[CH3:47])=[O:49])[CH2:53]1)=[NH:56]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(N(C=N)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC=N)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 7.2 %

Procedure:
A procedure similar to that described in Example 125 was repeated, but using 0.35 g of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and 0.22 g of (2S,4S)-4-mercapto-1-methyl-2-(3-[N-(4-nitrobenzyloxycarbonyl)-N-formimidoylamino]azetidin-1-ylcarbonyl)pyrrolidine (prepared as described in Preparation 118), to give 17 mg of the title compound as a powder.
Reaction SMILES: C[C@@H]1CNC[C@H](C)N1.ClC1N(C2C=CC=CC=2)N=NN=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29]2[N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=[N:31][N:30]=2)[CH2:23]1.[F:40][C:41]1[CH:46]=[N:45][C:44]([N:47]2[CH:51]=[CH:50][N:49]=[N:48]2)=[C:43]2[NH:52][CH:53]=[C:54]([C:55](=[O:59])[C:56](O)=[O:57])[C:42]=12>>[CH3:28][C@H:26]1[NH:27][C@@H:22]([CH3:21])[CH2:23][N:24]([C:29]2[N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=[N:31][N:30]=2)[CH2:25]1.[CH3:21][C@@H:22]1[CH2:23][N:24]([C:29]2[N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=[N:31][N:30]=2)[CH2:25][C@H:26]([CH3:28])[N:27]1[C:56](=[O:57])[C:55]([C:54]1[C:42]2[C:43](=[C:44]([N:47]3[CH:51]=[CH:50][N:49]=[N:48]3)[N:45]=[CH:46][C:41]=2[F:40])[NH:52][CH:53]=1)=[O:59]
Reactant: O=C(O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12
Agent: C[C@@H]1CN(c2nnnn2-c2ccccc2)C[C@H](C)N1
Agent: C[C@@H]1CNC[C@H](C)N1
Agent: Clc1nnnn1-c1ccccc1
Product: C[C@@H]1CN(c2nnnn2-c2ccccc2)C[C@H](C)N1C(=O)C(=O)c1c[nH]c2c(-n3ccnn3)ncc(F)c12

Procedure:
(3R,5S)-3,5-dimethyl-1-(1-phenyl-1H-tetrazol-5-yl)piperazine was prepared via method A in chemistry section 1 using (2R,6S)-2,6-dimethylpiperazine and 5-chloro-1-phenyl-1H-tetrazole. (3R,5S)-3,5-dimethyl-1-(1-phenyl-1H-tetrazol-5-yl)piperazine was coupled with 2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid using method B for the preparation of compound 3 in chemistry section A to provide the desired product 1-((2R,6S)-2,6-dimethyl-4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)-2-(4-fluoro-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione with the following characteristics:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[CH:7][N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:16].[C:17]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2N(C)C)CCCCC1.C1(C)C=CC=CC=1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2([CH3:1])[CH2:6][CH2:5][C:4](=[CH:7][N:8]([CH3:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]2=[O:16])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(C=C1CCC(C)(c2ccc(C(C)(C)C)cc2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 99.6 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with palladium acetate (5.6 mg, 0.025 mmol, 5 mol % Pd), (−)-2-(dicyclohexylphosphino)-2′-(dimethylamino)-1,1′-binaphthyl (18.5 mg, 0.038 mmol, 7.5 mol %) and 2-methyl-5-(N-methyl-anilinomethylene) cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 4-t-Butylbromobenzene (0.17 mL, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube, the tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 173 mg (99%) of the title compound. The ee was determined to be 67% by chiral HPLC analysis.
Reaction SMILES: C[Si]([NH:5][OH:6])(C)C.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:24])=[C:13]([C:19](OCC)=[O:20])[C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.O>CN(C)C=O>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:24])=[C:13]([C:19]([NH:5][OH:6])=[O:20])[C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C[Si](C)(C)NO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NO)c1c(O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
2 ml of trimethylsilylhydroxylamine (15 mmol) were sprayed at room temperature into a suspension of 2.64 g of ethyl 7-chloro-4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylate (10 mmol) in 2.0 ml of dimethylformamide. After heating to 100° C. all passed slowly into solution. The reaction mixture was left to stir at 80° C. for 2 hrs., cooled to room temperature and stirred overnight. After the addition of 6 ml of water a voluminous precipitate separated and was filtered off, washed with water and dried in a high vacuum. 1.48 g of 7-chloro-4,N-dihydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxamide (58%) were obtained as pale beige crystals.
Reaction SMILES: [ClH:1].[P:2]([O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:35]=[C:34]3[C:29]([C:30]([NH:36][C:37]4[S:38][C:39]([CH2:42][C:43]([NH:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[F:52])=[O:44])=[CH:40][N:41]=4)=[N:31][CH:32]=[N:33]3)=[CH:28][C:27]=2[O:53][CH3:54])[CH2:18][CH2:17]1)([O:9]C(C)(C)C)([O:4]C(C)(C)C)=[O:3]>O1CCOCC1>[ClH:1].[ClH:1].[P:2]([OH:9])([OH:4])([O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:35]=[C:34]3[C:29]([C:30]([NH:36][C:37]4[S:38][C:39]([CH2:42][C:43]([NH:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[F:52])=[O:44])=[CH:40][N:41]=4)=[N:31][CH:32]=[N:33]3)=[CH:28][C:27]=2[O:53][CH3:54])[CH2:18][CH2:17]1)=[O:3]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4ccccc4F)s3)ncnc2cc1OCCCN1CCC(COP(=O)(OC(C)(C)C)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4ccccc4F)s3)ncnc2cc1OCCCN1CCC(COP(=O)(O)O)CC1
Reaction time: 20 h
Yield: 84 %

Procedure:
Hydrochloric acid (1 ml of a 4.0 N solution in 1,4-dioxane, 4 mmol) was added, dropwise to a solution of di(tert-butyl) (1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl phosphate (assumed 379 mg, 0.49 mmol) in 1,4-dioxane (15 ml) upon which a light yellow solid precipitated from the reaction mixture. The resulting heterogeneous reaction mixture was stirred for a further 20 hours and the precipitate was filtered and washed with 1,4-dioxane (2×5 ml) then dried under high vacuum for 48 hours to furnish (1-(3-((4-((5-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl dihydrogen phosphate bis-hydrochloride as a light yellow solid (302 mg, 84% yield):
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:16])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]2[O:10][C:9]([C:11]([Cl:16])=[O:13])=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cc2cncc(Cl)c2o1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cl)c1cc2cncc(Cl)c2o1

Procedure:
7-Chloro-furo[3,2-c]pyridine-2-carboxylic acid (prepared according to the method of Example 132, Step A, 8.94 g, 45.2 mmol) was combined with thionyl chloride (30 mL) and sodium carbonate (9.59 g, 90.5 mmol) and heated to reflux for 16 h under nitrogen atmosphere. The cooled mixture was diluted with dichloromethane and filtered. The filtrate was evaporated to give the title compound of Example 132, Step B as an orange oil, 9.19 g (94%). The acid chloride was used directly without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:11][CH:10]=2)[CH3:2].[H-].[Na+].[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([C:42]2[CH:53]=[CH:52][C:45]([CH2:46]OS(C)(=O)=O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]1[N:8]([CH2:46][C:45]2[CH:44]=[CH:43][C:42]([C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)=[CH:53][CH:52]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:11][CH:10]=2)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1[nH]c2ccc(OCc3ccccn3)cc2c1SC(C)(C)C
Reactant: COc1ccc(-c2ccc(COS(C)(=O)=O)cc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
3-[3-tert-Butylsulfanyl-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (A-4; 20.0 g, 45.4 mmol) was dissolved in DMF (150 mL) and cooled to −10° C. under N2. Sodium hydride (60% dispersion in mineral oil, 2.0 g, 50.0 mmol) was added portionwise, and the reaction was stirred at −10° C. for 45 minutes until the foam had disappeared. To this dark brown-reddish solution was added methanesulfonic acid 4-(6-methoxy-pyridin-3-yl)-benzyl ester (Int-72; 16.0 g, 54.5 mmol) in DMF dropwise. The reaction was then stirred at −10° C. for 1 hour and allowed to warm to room temperature slowly. After 16 hours, LCMS confirmed the formation of the product. The reaction was quenched with saturated NH4Cl and diluted with methyl tert-butyl ether (MTBE) and water. The aqueous phase was extracted twice with MTBE. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude product was purified by column chromatography to give the desired product (A-5).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]=1)=[O:4].CO[CH2:20][N:21]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:27]([N:21]1[CH2:22][C@@:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@H:6]2[CH2:20]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)C1=CC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]12C[C@H](NC(=O)OC(C)(C)C)C[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step B (5.51 g, 20 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (6.4 mL, 24 mmol, Aldrich) in DCM (40 mL) was added 1M TFA in DCM (2.4 mL, 2.4 mmol) slowly. The resulting mixture was stirred at rt overnight and quenched by the addition of saturated aqueous NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4. Evaporation and purification by column chromatography (eluent: 10% EtOAc in hexanes to 20%) gave the desired isomer as a colorless gel. 1H-NMR (400 MHz, CDCl3) of the desired isomer: δ 1.38 (s, 9H), 1.66-1.86 (m, 2H), 1.86-1.96 (m, 1H), 1.96-2.08 (m, 1H), 2.29-2.63 (m, 3H), 2.71-2.93 (m, 2H), 3.43-3.56 (m, 2H), 3.58-3.74 (s, 3H), 4.08-4.29 (m, 1H), 4.78 (d, J=6.6 Hz, 1H), 7.11-7.31 (m, 5H). LC/MS: C24H28N2O4: m/z 375.2 (M+H).
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
0.34 g. of 1-benzyloxy-2-[(2,6-dichlorophenyl)-imino]imidazolidine is hydrogenated under normal pressure in 5 ml. of ethanol and 2 ml. of 1 N hydrochloric acid in the presence of 0.05 g. of palladium-on-charcoal (5%). After the uptake of hydrogen has ended, the catalyst is filtered off and the solution is evaporated. The residue is dissolved in water and the solution is adjusted to pH 10 with caustic soda solution and extracted, first with methylene chloride and then with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from acetonitrile, whereupon 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine, m.p. 196°, is obtained. Recrystallization from methanol/acetonitrile raises the melting point to 215°.