Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH3:4][N:5]([C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19]CC)=[O:18])[C:6]([O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7].[OH-].[Na+].Cl>C(OCC)(=O)C>[CH3:4][N:5]([C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([OH:19])=[O:18])[C:6]([O:8][CH2:9][C:10]([Cl:11])([Cl:13])[Cl:12])=[O:7]
Reactant: CCOC(=O)c1cccc(N(C)C(=O)OCC(Cl)(Cl)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C(=O)OCC(Cl)(Cl)Cl)c1cccc(C(=O)O)c1
Yield: 97.7 %

Procedure:
To 5 ml of ethanol were added 0.5 g of ethyl 3-[N-methyl-N-(2,2,2-trichloroethoxycarbonyl)amino]benzoate and a 1N sodium hydroxide aqueous solution, and the resultant mixture was stirred at room temperature for 1.5 hours. After the reaction solution was controlled to pH 3 by dropwise adding 1N hydrochloric acid, ethyl acetate was added to the reaction solution, and an organic layer was separated. The organic layer was washed with water twice and washed with a saturated saline solution once, and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.45 g (yield 98%) of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>C(Cl)Cl.C1(NN)C=CC=CC=1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[CH2:16]([O:15][C:13]([C@@H:12]1[CH2:7][C@H:6]1[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(Br)cc1
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Solvent: NNc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
Copper(II) acetylacetonate (0.156 g, 0.6 mmol) was dissolved in CH2Cl2 (40 mL) then phenylhydrazine (3 drops, catalytic amount) was added. After 5 minutes, 4-bromostyrene (2.6 mL, 20 mmol) was added and the reaction was heated to 40° C. Ethyl diazoacetate (3.1 mL, 30 mmol) in CH2Cl2 (40 mL) was slowly added using a syringe pump. The reaction was stirred at 40° C. overnight then cooled and submitted to standard aqueous workup. The crude material was purified on silica gel (0-10% EtOAc in hexanes) two times to afford a separable mixture of two cyclopropyl isomers (cis- and trans-) and the less polar isomer was determined to be the title compound.
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]2)=[CH:13][C@@H:12]4O)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=O)[CH2:32][CH3:33])(=[O:29])CC>N1C=CC=CC=1.C(Cl)Cl>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]2)=[CH:13][C@@H:12]4[C:26]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[CH2:2][CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Reactant: CCC(=O)OC(=O)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOC(=O)[C@H]1C=C2NC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](OC4CC4)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a manner analogous to the procedure reported in Baer, H. et al., Can. J. Chem 1991, 69, 1563-1574, 17β-cyclopropyloxy-7β-hydroxy-4-aza-androst-5-en-3-one (1.000 g, 2.895 mmol) from Example 20A or otherwise obtained is dissolved in pyridine (20 mL). Proprionic anhydride (20.0 mL, 156.0 mmol) is added, and the mixture is stirred at room temperature under nitrogen for 12 hours. At the end of the reaction time, the solution is diluted with CH2Cl2 (150 mL) and washed with water (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4, filtered and evaporated to dryness. The residue is purified by flash chromatography (1:1 EtOAc/CH2Cl2) to give the title compound.
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[CH2:24][CH2:25][CH3:26].[C:27](OC(=O)C)(=[O:29])[CH3:28].CO>ClCCl>[C:27]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:23])([C:15]([F:16])([F:17])[F:18])[C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]=1[CH2:24][CH2:25][CH3:26])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1O
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OC(C)=O
Reaction time: 8 h
Yield: 87 %

Procedure:
Pyridine (14.7 mL) was added to 2-(4-hydroxy-3-propylphenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (13.76 g, 45.5 mmol) in dichloromethane (200 mL) at room temperature, and then acetic anhydride (17.3 mL) was added. After stirring overnight, methanol (300 mL) was added. After stirring at room temperature for one hour, the reaction solution was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 13.67 g of the title compound (yield: 87%) as a red brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][C:5]=1[O:13][CH2:14][CH3:15])[CH3:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[C:16](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[O:22])[CH3:12]
Reactant: CCOc1ccc(OCC)c(OCC)c1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(OCC)c(C(=O)/C=C/C(=O)O)cc1OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.1 parts by weight of 1,2,4-triethoxybenzene, 1.2 part by weight of maleic anhydride and 30 parts by volume of carbon tetrachloride is added 5.2 parts by weight of anhydrous aluminum chloride. The mixture is stirred for 1 hour and heated at 50° C for another 1 hour. After cooling, concentrated hydrochloric acid and ice are added to the mixture. The mixture is extracted with methylenechloride and the methylenechloride layer is washed with water and dried over anhydrous sodium sulfate. Upon removing the solvent by distillation, 3-(2',4',5'-triethoxybenzoyl)-trans-acrylic acid is obtained as crystals. Recrystallization from a mixture of ethanol and benzene gives yellow needles melting at 192°-194° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](F)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CS(C)=O.[Cl-].[Na+].O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:32][C@H:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=2)[CH3:31])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C

Procedure:
To a suspension of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (30.0 mg, 0.106 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (38.4 mg, 0.159 mmol) in DMSO (0.53 mL), was added DIEA (64.7 ul, 0.371 mmol) in a microwave vial. The vial was capped and the reaction mixture heated in a preheated oil bath at 100° C. for 3 hr. The mixture was diluted with dilute brine and extracted with EtOAc two times. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a clear colorless oil which was used without further purification (yield assumed quantitative). LCMS m/z 469.3 (M+H)+, Rt 0.98 min.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH:27]4[CH3:34])=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:37]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH:27]5[CH3:34])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:35][CH:36]=2)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC1C(=O)NS(=O)(=O)N1c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC1C(=O)NS(=O)(=O)N1c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-methyl-1, 2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-methyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Mg]Br)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]2([OH:26])[CH2:24][CH2:25][N:21]([CH2:20][C:19]3[CH:27]=[CH:28][CH:29]=[C:17]([O:16][CH3:15])[CH:18]=3)[CH2:22]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc(CN2CCC(=O)C2)c1
Reactant: Clc1ccc(I)cc1Cl
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1cccc(CN2CCC(O)(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 3,4-dichloro-1-iodobenzene (1.33 g, 4.90 mmol) in tetrahydrofuran (10 mL) at room temperature, was added isopropylmagnesium bromide (2.4 mL of a 2.0 M solution in THF, 4.9 mmol) dropwise. After 2 h, a solution of 1-(3-methoxybenzyl)pyrrolidin-3-one (500 mg, 2.43 mmol) from Step B above in tetrahydrofuran (3 mL) was added dropwise at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride (5 mL). The mixture was diluted with ethyl acetate (100 mL) and washed with saturated ammonium chloride (20 mL), water (20 mL), and brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (5% ethyl acetate/methylene chloride to 80% ethyl acetate/methylene chloride) gave 3-(3,4-dichlorophenyl)-1-(3-methoxybenzyl)pyrrolidin-3-ol (500 mg, 58%) as a yellow oil: ESI MS (m/z) 352 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.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>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])c1
Reactant: Cc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc([N+](=O)[O-])c1

Procedure:
To a stirred solution of methyl 3-iodo-5-nitrobenzoate (7.76 g, 24 mmol) and p-tolylboronic acid (3.94 g, 28 mmol) in toluene (576 mL) was added cesium carbonate (9.4 g, 28 mmol) in water (7.8 mL). The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (860 mg, 0.74 mmol) was added at room temperature. The reaction mixture was heated to reflux for 3 days. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford a white solid.
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28](N(C)C)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:13]=1)=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C(=O)c1ccccc1OCc1ccccc1
Reactant: c1ccc(-c2ccccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Temperature: -10 °C

Procedure:
To a solution of 12.9 g (145 mmol) of 2-N,N-dimethylaminoethanol in 100 mL of hexanes, 116 mL (290 mmol) of 2.5 M nBuLi in hexanes was added dropwise with vigorous stirring at −10° C. This mixture was slowly warmed to 0° C., stirred for 30 min, and then 7.54 g (48.6 mmol) of 2-phenylpyridine was added at −10° C. The resulting mixture was stirred for 2 hr at 0° C. and then added dropwise to a solution of 43.2 g (179 mmol) of 16 in 725 mL of THF at −10° C. This mixture was slowly warmed to room temperature, stirred for 12 hr, and then 20 mL of water was added. The organic solvent was evaporated using a rotary evaporator. 17 was isolated from the residue by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-ethyl acetate=5:1, vol.). The obtained product was additionally washed with 30 mL of diethyl ether and then dried in vacuum. Yield 11.0 g (62%) of white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:19][F:20])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.CN(C)CCN(C)C.[C:53]1([Se:59]Cl)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:19][F:20])[CH2:13][C@H:14]([Se:59][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Reactant: Cl[Se]c1ccccc1
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)[C@H](CC(CF)NC(=O)OCc1ccccc1)[Se]c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1.42 g of 13 in 25 ml of dry tetrahydrofuran was added drop-by-drop to a solution of lithium hexamethyldisilazide (prepared by adding 5.7 ml of a 2.2M solution of n-butyllithium in hexane drop-by-drop to a solution of 2.7 ml of hexamethyldisilazane and 1.9 ml of tetramethylethylenediamine in tetrahydrofuran) in 15 ml of dry tetrahydrofuran, at -78° C., under argon. The resulting solution was stirred for one hour at -78° C., then a solution of 0.96 g of phenylselenenyl chloride in 15 ml of dry tetrahydrofuran was added rapidly. The resulting solution was stirred at -78° C. for 10 minutes, warmed to -20° C. and quenched by the addition of 60 ml of 1N hydrochloric acid and 20 ml of cold water. The solution then was warmed to room temperature and extracted with ether. The extract was washed, successively, with water, 1N hydrochloric acid, 1N sodium bicarbonate solution and water. It then was dried (MgSO4), the solvent was evaporated and the residue was chromatographed on silica gel, eluting first with n-hexane (to remove diphenylselenide) and then with 30% ethyl acetate/n-hexane to give, on work-up, methyl (S)-4-(benzyloxycarbonylamino)-5-fluoro-2-(phenylselenyl)pentanoate (26A), as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].COC(O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCc2ccncc2)c1
Agent: COC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1cccc(S(=O)(=O)NCc2ccncc2)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
A mixture of 3-nitro-N-(pyridin-4-ylmethyl)-benzenesulfonamide [CAS No. 332942-34-4, commercially available] (1.23 g, 4.2 mmol), sodium dithionite (3.09 g, 15.1 mmol), water (10 ml) and 2 methoxyethanol (10 ml) was stirred at 100° C. for 2 h, additional water (7 ml) was added at 70° C. and subsequently HCl (37%, 7 ml) was added over a period of 10 min (SO2 evolution). The reaction mixture was stirred at 70° C. for 20 min, poured into ice/water (50 ml) and sodium carbonate was added until the solution proofed to be basic. The solution was extracted with ethyl acetate/MeOH 9:1 (3×75 ml), the combined organic layers washed with brine (80 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (MeOH/ethyl acetate 1:9) to yield the title compound (0.8 g, 72%) as a light yellow solid. MS (ISP) 261.9 [(M−H)−]; m.p. 139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C1(C)C=CC=CC=1>[C:29]([NH:28][C:26]1[S:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=4[NH:1][C:32](=[O:34])[CH3:33])[CH:13]=3)[C:24]=2[N:25]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(C)=O)ncn3)cccc2s1
Temperature: 25 °C

Procedure:
To a suspension of N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.20 g, 0.50 mmol) in toluene (10 mL) was added acetic anhydride (0.090 g, 0.80 mmol, Aldrich). The reaction mixture was heated at reflux for 3 h, allowed to cool to room temperature and concentrated in vacuum. The residue was dissolved in EtOAc (20 mL) and washed with satd NaHCO3 (2×20 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (1:1:0.5 CH2Cl2/hexanes/EtOAc) provided the title compound as an off-white solid. Mp: 259–261° C. MS (ESI, pos. ion) m/z: 488 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][CH:40]=1)[O:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:35]=[C:34]([CH3:36])[C:18]([O:19][CH:20]4[CH2:23][CH:22]([C:24]([O:26]CC5C=CC=CC=5)=[O:25])[CH2:21]4)=[C:17]([CH3:37])[CH:16]=3)[O:12][C:10]=2[N:11]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][CH:40]=1)[O:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:35]=[C:34]([CH3:36])[C:18]([O:19][CH:20]4[CH2:23][CH:22]([C:24]([OH:26])=[O:25])[CH2:21]4)=[C:17]([CH3:37])[CH:16]=3)[O:12][C:10]=2[N:11]=1
Reactant: Cc1cc(-c2nc3cnc(Oc4cccc(Cl)c4)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc3cnc(Oc4cccc(Cl)c4)nc3o2)cc(C)c1OC1CC(C(=O)O)C1
Reaction time: 5 h
Yield: 31 %

Procedure:
77 mg of benzyl 3-{4-[5-(3-chlorophenoxy)oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}cyclobutanecarboxylate were dissolved in 4.4 ml of ethyl acetate, 2.5 mg of palladium on carbon (5%) were added and the mixture was hydrogenated at 3 bar and room temperature. After 5 h, the catalyst was filtered off. The filtrate was concentrated, and purification by preparative HPLC gave 20 mg (32%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([OH:11])[CH2:9][CH3:10])=[CH:6][N:5]=[C:4]2[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:3]=12>COCCOC.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][N:5]=[C:4]2[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:14][C:3]=12
Reactant: CCC(O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: COCCOC
Product: CCC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1Cl
Reaction time: 3 h
Yield: 53 %

Procedure:
1-(4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)propan-1-ol (75.6 mg, 0.222 mmol) in 1,2-dimethoxyethane (5 mL) was vigorously stirred with manganese dioxide (450 mg, 5.17 mmol) at 60° C. for 3 hours and then at 80° C. for 3 hours. The reaction mixture was filtered, the solid was washed with chloroform, and the filtrate and the washings were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1 (v/v)) to give the title compound as a colorless oil (39.9 mg, yield 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18]C)=[O:17])[C:6]2=[O:24].[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([OH:18])=[O:17])[C:6]2=[O:24]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(OC)cc3c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2ncn(-c3cc(C(=O)O)ccc3C)c(=O)c2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a stirred suspension of methyl 3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate (19.3 g) in a mixture of methanol (650 ml) and water (150 ml) was added 2N NaOH (89 ml) and heated to 70° C. until a clear solution was formed at which point the heating stopped. Stirring was continued for a further 1.5 hours. The pH was adjusted to pH˜1 with 1N HCl and the resultant solid collected by filtration. The solid was dried in vacuo for 16 hours to yield 3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoic acid as a white solid (17.8 g); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 3.88 (s, 3H), 7.49 (m, 1H), 7.57 (m, 2H), 7.71 (d, 1H), 7.93 (s, 1H), 7.98 (m, 1H), 8.20 (s, 1H); Mass Spectrum: M+H+ 311.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16](=[O:24])[CH:15]2[CH2:25][C:26]([O:28]C)=[O:27])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10]>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16](=[O:24])[CH:15]2[CH2:25][C:26]([OH:28])=[O:27])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)CC1C(=O)Nc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1C(=O)Nc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 48 h

Procedure:
Lithium hydroxide (0.041 g, 10.95 mmol) was added to a cooled solution of methyl 2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)acetate (2.7 g, 7.3 mmol) in THF (45 ml) and water (45 ml), and stirring was carried out for 48 h at room temperature (TLC monitoring). The solvent was removed using a rotary evaporator and the residue was taken up in water. The aqueous phase was extracted with ethyl acetate and then washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated to dryness.