Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][CH:4]([CH3:9])[S:3]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.C([SiH](CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:6]1[CH2:7][CH:2]([CH3:1])[S:3][CH:4]([CH3:9])[CH2:5]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: CC1CC(=O)CC(C)S1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CC(C)SC(C)C3)c[nH]c12
Temperature: 0 °C
Yield: 26.3 %

Procedure:
2,6-Dimethyltetrahydro-4H-thiopyran-4-one (0.293 g, 2.03 mmol) was dissolved in dichloromethane (35 mL) in an oven dried flask containing 3 Å molecular sieves and stirred under argon at 0° C. TMS-OTf (0.451 g, 2.0 mmol, 0.36 mL) was added slowly to the mixture over 10 min. Ethyl 5-bromo-1H-indole-7-carboxylate (0.293 g, 2.031 mmol) was dissolved in DCM (10 mL) and added to the reaction via syringe pump over 2 hours, after which it was stirred for 3 hours between 0 and 10° C. The reaction was cooled to 0° C. and triethylsilane (0.353 g, 0.485 mL, 3.04 mmol) was then added all at once and the reaction was stirred at room temperature overnight. The reaction was then quenched with a saturated sodium bicarbonate solution, filtered, then extracted with DCM. The combined organics were washed with water. The combined aqueous layers were back-extracted with DCM. The combined organics were washed with brine, dried with MgSO4, and concentrated. The crude compound was purified on Combiflash silica column with 0-30% EA/DCM to give 0.212 g (26%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:14].O[CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[NH2:18]>>[ClH:14].[CH2:1]([NH:13][CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCN
Agent: Cl
Product: CCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C

Procedure:
46 g of dodecylamine were melted at 60° and 31 g of glucosamine hydrochloride were added with stirring. After cooling down to room temperature, the product precipitated out. The solid material was stirred thoroughly three times with ether and filtered off with suction and subsequently dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([N:23](C)[CH3:24])[C:13]([O:21][CH3:22])=[C:14]([CH:20]=2)[N:15]([CH3:19])[C:16](=O)C)=[CH:4][N:3]=1.Cl>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([NH:23][CH3:24])[C:13]([O:21][CH3:22])=[C:14]([N:15]([CH3:19])[CH3:16])[CH:20]=2)=[CH:4][N:3]=1
Reactant: COc1c(N(C)C)cc(Cc2cnc(N)nc2N)cc1N(C)C(C)=O
Agent: Cl
Product: CNc1cc(Cc2cnc(N)nc2N)cc(N(C)C)c1OC

Procedure:
4.0 G. of 5'-[(2,4-diamino-5-pyrimidinyl)methyl]3'-dimethylamino-2'-methoxy-N-methylacetanilide (prepared as described in the first paragraph of Example 2) and 100 ml. of 1-N hydrochloric acid were boiled under reflux for 2 hours. After neutralization and evaporation in vacuo, purification of the residue over silica gel with methylene chloride/propanol (8:2) and recrystallization from ethanol, there was obtained 2,4-diamino-5-[3-dimethylamino-4-methoxy-5-(methylamino)benzyl]pyrimidine, having a melting point of 183° C.
Reaction SMILES: [N+:1]([C:4]1[CH:59]=[CH:58][C:7]([CH2:8][O:9][C:10]([CH2:12][NH:13][C:14]([C:16]2[N:17]=[C:18]([N:21]3[CH2:24][CH:23]([S:25][C:26]4[C@H:27]([CH3:57])[C@@H:28]5[C@@H:45]([C@H:46]([O:48][Si](C(C)(C)C)(C)C)[CH3:47])[C:44](=[O:56])[N:29]5[C:30]=4[C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:22]3)[S:19][CH:20]=2)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:59]=[CH:58][C:7]([CH2:8][O:9][C:10]([CH2:12][NH:13][C:14]([C:16]2[N:17]=[C:18]([N:21]3[CH2:24][CH:23]([S:25][C:26]4[C@H:27]([CH3:57])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:56])[N:29]5[C:30]=4[C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:22]3)[S:19][CH:20]=2)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCC(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCC(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.3 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(p-nitrobenzyloxycarbonylmethyl-carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (209.7 mg, 0.24 mmol) (obtained as described in Reference Example 41(10)) in tetrahydrofuran (10 ml) was added acetic acid (0.042 ml, 0.7 mmol) and 1 M tetrabutylammonium fluoride in tetrahydrofuran solution (0.72 ml, 0.72 mmol) in an ice bath and the mixture was stirred at room temperature for 4 days. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: toluene: acetonitrile (2:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(p-nitrobenzyloxycarbonylmethyl-carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (94.5 mg, yield 53%) as a pale yellow solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]1[CH2:22][CH2:21][CH:20]2[CH:15]([CH2:16][CH:17]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]2)[CH2:14]1.C(OCC)C>C(Cl)Cl>[O:12]=[C:13]1[CH2:22][CH2:21][CH:20]2[CH:15]([CH2:16][CH:17]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]2)[CH2:14]1
Reactant: CCOC(=O)C1CC2CC(O)CCC2CN1C(=O)OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A mixture of 146.1 g of pyridinium chlorochromate, 146.1 g of powdered 4 Å sieves, and 1000 ml of methylene chloride was stirred for 1 hour at room temperature. A solution of 87.9 g of ethyl decahydro6-hydroxy-2-methoxycarbonyl-3-isoquinolinecarboxylate in 30 ml of methylene chloride was added dropwise in 200 ml of dichloromethane and the reaction mixture stirred for three hours at room temperature. Diethyl ether (1400 ml) was added to the mixture which was then filtered through a Celite® pad and silica gel pad. The filtrate was concentrated in vacuo, redissolved in diethyl ether, and again filtered through Celite and silica gel. Concentration of the filtrate afforded 78.4 g of the desired title product as a 28:72 mixture of equitorial: axial ester isomers. The residue was dissolved in 600 ml of ethanol, 1.11 g of sodium hydride dissolved in 60 ml of ethanol was added, and the mixture heated at 80° C. for 2.25 hours. The mixture was cooled and concentrated in vacuo. To the residue were added 700 ml of 1:1 dichloromethane/diethyl ether and this solution was washed with 300 ml of 10% aqueous sodium bisulfate. The organic layer was separated and the aqueous layer extracted three times with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was filtered through silica gel with 40% ethyl acetate in hexane, and the filtrate was concentrated in vacuo to afford an oil. Crystallization from ether/hexane afforded 32.3 g of the desired subtitled intermediate, m.p. 79°-80° C., that was one compound by as determined by gas chromatography. By 1H NMR and X-ray crystallographic analysis, this ketone was determined to be ethyl 1a-R*-3-R*-4a-R*-decahydro-6-oxo-2-methoxycarbonyl-3-isoquinolinecarboxylate. It is assumed that this stereochemistry carries forward to each of the final products.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12]C=O)([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:15].Cl.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(CC(C)(C)NC=O)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(CC(C)(C)N)ccc1F

Procedure:
4.3 g (20.6 mmol) of N-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethyl]formamide, 20 mL concentrated hydrochloric acid, and 20 mL water are refluxed for 2 hours. The reaction mixture is diluted with water, made alkaline with concentrated sodium hydroxide solution, and extracted with dichloromethane. The organic phases are dried with sodium sulfate and evaporated down. The residue is dissolved in ethyl acetate, combined with ethereal hydrochloric acid, and cooled. The crystals precipitated are suction filtered and washed with diethyl ether and dried. White solid. Yield: 3.9 g (87%, hydrochloride); melting point 196° C.-198° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].O.[C:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>CC(C)=O>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[C:11]([OH:13])=[O:12])=[O:24])=[CH:26][CH:27]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(C(=O)O)cc1C(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2C(=O)O)cc1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
Into 60 mL acetone was dissolved 0.905 g (5 mmol) 4-aminoisophthalic acid. To the solution was added 30 mL water. The mixture was cooled in an ice bath, and 1.08 mL (5.5 mmol) 4-tert-butylbenzoyl chloride in 10 mL acetone was added dropwise. The mixture was allowed to warm slowlyly to room temperature and after 24 h was concentrated under vacuum and shaken between EtOAc (150 mL) and cold dilute HCl (150 mL). The organic layer was dried (MgSO4) and evaporated. The desired crystalline product (0.489 g, 29%) was obtained from methylene chloride-hexane.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:8]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)C.N>CN(C)C=O>[C:13]1([C:10]2[N:11]=[N:12][C:7]([C:29]#[C:28][C:30]3([OH:38])[CH:35]4[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]4)[CH2:31]3)=[C:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Oc1nnc(-c2ccccc2)cc1Cc1ccccc1)C(F)(F)F
Reactant: C#CC1(O)CN2CCC1CC2
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2nnc(-c3ccccc3)cc2Cc2ccccc2)CN2CCC1CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of 484 mg of 3-phenyl-5-benzyl-6-pyridazyl trifluoromethane sulfonate, 223 mg of 3-ethynyl-3-quinuclidinol, 284 mg of tetrakis (triphenylphosphine)palladium(0), 47 mg of cuprous iodide, 513 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 80° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1) and then crystallized from hexane/ethyl acetate, to give 413 mg of the target compound.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]([C:8]([OH:10])=[O:9])[CH2:2]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[S:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]([C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: O=C(O)C1CSCCC1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C(O)C1CSC=CC1=O

Procedure:
To a solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (Example 4, step A) (2.3 g, 11.5 mmol) in 100 mL dry chloroform at room temperature was added activated manganese dioxide (10 g, 115 mmol) and the resulting mixture was refluxed for 5 h. The reaction mixture was filtered and evaporated. The the remaining residue was purified by flash column chromatography on silica gel eluted with hexane:ethyl acetate (7:3) to give 2,3-dihydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.988 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[N:9]=[CH:8]2.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[N:9]=[CH:8]2
Reactant: COc1cccc2cnc(C)nc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of 8-methoxy-2-methylquinazoline (1.50 g) in dichloromethane (10 ml) was added 1M solution of boron tribromide in dichloromethane (12.9 ml) at 3°-5° C. After 10 minutes, the reaction mixture was stirred at ambient temperature for 2 days. The mixture was adjusted to pH 7 with saturated sodium hydrogen carbonate, and extracted with dichloromethane twice. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was crystallized from n-hexane to give 8-hydroxy-2-methylquinazoline (1.22 g) as colorless crystals.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[C:22]([Br:23])=[CH:21][C:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][N:18]=2)=[CH:11][CH:10]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.BrCl>>[Br:23][C:22]1[C:17]([C:16]#[C:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:35]3[CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:10][CH:11]=2)=[N:18][CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:21]=1
Reactant: CC1CCNCC1
Reactant: CS(=O)(=O)OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2Br)cc1
Agent: ClBr
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3Br)cc2)CC1

Procedure:
The product was obtained analogously to Example 7.1g starting from 2-{4-[3-bromo-5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl methanesulfonate and 4-methylpiperidine. Yield: 0.15 g (88% of theoretical); C27H26BrClN2O (M=509.865); calc.: molpeak (M+H)+: 509/511/513 (BrCl); found: molpeak (M+H)+: 509/511/513 (BrCl); HPLC-MS: 6.11 minutes (method A).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C@H:10]([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12].C(OCC)(=O)C>C1COCC1.C(O)(C)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C@H:10]([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:16])([F:17])[F:18])=[O:12])[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: C[C@@H](N)C(=O)NCC(F)(F)F
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](Nc1ncnc(Cl)n1)C(=O)NCC(F)(F)F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (298 mg, 2.0 mmol) in 4 mL THF and isopropanol(1:1 v:v) at −20° C. was added (R)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (412 mg, 2.0 mmol, 1.0 equiv.), followed by the addition of N,N-isopropyl ethyl amine (516 mg, 4.0 mmol, 2.0 equiv.). The reaction was stirred at −20° C. for 20 minutes then was allowed to warm to room temperature. After 30 minutes, the reaction was poured into ethyl acetate and washed with water. The organic layer was concentrated. The oily residue was purified by chromatography (2:1 hexane/ethyl acetate) to produce 186 mg of (R)-2-(4-chloro-1,3,5-triazin-2-ylamino)-N-(2,2,2-trifluoroethyl)propanamide (compound 1034) (LC/MS: MS+1=284.1, MS−1=282.3, R.T.=1.5 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[O:20]1[C:24]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)=[CH:23][CH:22]=[N:21]1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:24]1[O:20][N:21]=[CH:22][CH:23]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: O=Cc1ccccc1-c1ccno1
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1c(-c2ccccc2-c2ccno2)nc2cc(-c3cnc(N)nc3)ccc21
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (74 mg, 029 mmol) in DMF (10 mL) is added 2-isoxazol-5-yl-benzaldehyde (60 mg, 0.29 mmol) at room temperature. Oxone (177 mg, 0.29 mmol) in H2O (1 mL) is added and the solution is stirred at the same temperature for 3 hours. Saturated sodium thiosulfate (10 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried with MgSO4 (1 g) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (37 mg, 31%). LCMS (ESMS): m/z: 411.40 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Cl:17])[CH:11]=1)([OH:9])[C:6]([OH:8])=[O:7].[CH2:22]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Cl:17])[CH:11]=1)([OH:9])[C:6]([O:8][CH3:22])=[O:7]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(O)(c1ccc(F)c(Cl)c1)c1ccc(F)c(Cl)c1
Solvent: CI
Solvent: CC#N
Product: COC(=O)C(O)(c1ccc(F)c(Cl)c1)c1ccc(F)c(Cl)c1

Procedure:
17.07 g (0.0512 mol) of 3,3′-dichloro-4,4′-difluorobenzilic acid, 14.10 g (0.0926 mol) of DBU, and 26.29 g (0.1852 mol) of methyl iodide are reacted in 200 ml acetonitrile analogously to step I.10.3. Yield: 6.77 g (38% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[C:16](OC=O)(=[O:18])C>>[CH:16]([NH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1)=[O:18]
Reactant: CCOC1=NS(=O)(=O)c2cc(N)ccc21
Reactant: CC(=O)OC=O
Product: CCOC1=NS(=O)(=O)c2cc(NC=O)ccc21

Procedure:
Following the procedures outlined in Description 4a, 6-amino-3-ethoxy-benzoisothiazole-1,1-dioxide was reacted with formic-acetic anhydride to give the title compound.
Reaction SMILES: F[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:25]=1)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1.[C:35](C1C=CC(OCC2C=CC(C(C3C=C(C=CC=3)C#N)C)=CC=2)=C(CCC)C=1O)(=O)C>>[OH:18][C:11]1[C:10]([CH2:19][CH2:20][CH3:21])=[C:9]([O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([CH:2]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:34][N:33]=[N:32][N:31]=4)[CH:25]=3)[CH3:35])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[C:15](=[O:17])[CH3:16]
Reactant: CCCc1c(OCc2ccc(C(F)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(C)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(C)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared essentially as described for 1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone employing 3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-ethyl}-benzonitrile. The title compound is obtained (12.5 mg, 45%) as a white solid. 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 8.00 (s, 1H), 7.75-7.85 (m, 2H), 7.35-7.54 (m, 6H), 6.73 (d, 1H), 5.23 (s, 2H), 4.32 (m, 1H), 2.55-2.60 (m, 5H), 1.66 (d, 3H), 1.46-1.50 (m, 2H), 0.87 (t, 3H). LCMS M+1 457.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][N:15]=[C:16]([C:18]2[C:22]([OH:23])=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[N:20]([CH3:34])[N:19]=2)[CH3:17])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+].Cl>C1COCC1.O>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][N:15]=[C:16]([C:18]2[C:22]([OH:23])=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=3)[N:20]([CH3:34])[N:19]=2)[CH3:17])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)c(Br)c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 50 °C
Reaction time: 14 h
Yield: 64.6 %

Procedure:
To methyl 2-bromo-4-[(2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.455 mmol, 239.8 mg), methanol (20 mL) was added, and 1 M aqueous sodium hydroxide (2.3 mmol, 2.3 mL) was added. After 5 hours of stirring at 50° C., 14 hours of stirring at room temperature and 4 hours of stirring at 50° C., 1 M hydrochloric acid (2.3 mmol, 2.3 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the crude desired product as a yellow solid (203.8 mg). Further, 178 mg of the crude desired product was dissolved in THF (35 mL) and stirred at room temperature for 2 days. The insolubles were filtered off, and the filtrate was concentrated and dried by means of a vacuum pump. After addition of chloroform, the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (150.9 mg, yield 74%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Oc1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc(F)c2)C1
Yield: 98.1 %

Procedure:
The title compound (D47) (294.6 mg) was prepared according to the experimental procedure described in Description 40 starting from (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.068 mmol, available at Aldrich#634786) and 3-Fluorophenol (0.096 ml, 1.068 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:36](=[O:38])[CH3:37])=[CH:17][CH:18]=3)=[CH:9][N:8]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(CN)cc3)c3cc(Br)cnc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzylamine (Intermediate CB, 45 mg, 0.1 mmol) was combined with triethylamine (45 μl, 0.3 mmol) and acetic anhydride (11 μl, 0.11 mmol) in anh. DCM (2 ml). The mixture was stirred for 2 hrs, EtOAc, was added and washed with 0.5 N HCl, saturated NaHCO3, water and brine. Evaporation yielded the title compound (48 mg, 96%). MS ESI (m/z): 498.1/500.1 (M+1)+, calc. 497/499.