Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC([O-])=O.[Na+].[Br:16]Br.[OH-].[Na+]>CC(O)=O.C(Cl)Cl.O>[Br:16][C:8]1[CH:9]=[C:10]2[C:2]([CH3:1])=[N:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1n[nH]c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.4 %

Procedure:
To a solution of 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) (12.7 Kg, 95.4 mol) in HOAc (57 L) was added NaOAc (20.4 Kg, 248 mol), water (13.3 L), and Br2 (40 L, 780 mol). The reaction was stirred at room temperature for 5 hours and then at 115° C. for 6 hours. The reaction was cooled to room temperature and diluted with DCM (686 L). To this solution was added water (508 L) and cooled to 0° C. followed by dropwise addition of aqueous 30% NaOH while maintaining the temperature <20° C. under pH=9. The mixture was filtered through diatomaceous earth (14 Kg) followed by washing the diatomaceous earth with 3×DCM (50 L). The organic layer was separated, washed with aqueous 25% NaCl (200 L) and concentrated under vacuum to a volume of 70 L. The product was crystallized by charging the solution with 3×n-heptane (88 L) while concentrating the volume to 70 L after each addition of n-heptane. The solid was filtered and washed 3×n-heptane (22 L). The solid was dried under vacuum at 45° C. to yield 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (X) (9.8 Kg, 46.2 mol, 92.6% purity, 48.4% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.48 (s, 3H), 8.50-8.55 (m, 2H), 13.42 (brs, 1H); ESIMS found C7H6BrN3 m/z 213.7 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:16]=2)[C:11]([NH:31][C@@H:29]([C:26]2[CH:27]=[N:28][C:23]([C:22]([F:33])([F:21])[F:32])=[CH:24][CH:25]=2)[CH3:30])=[O:13])=[N:6][CH:7]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C(F)(F)F)nc3)cc(S(C)(=O)=O)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged 3-(5-methylpyridin-2-yl)-5-(methylsulfonyl)benzoic acid (40% mixture with BaCl2, 250 mg, 0.34 mmol), (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (130 mg, 0.69 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (130 mg, 0.69 mmol), 1-hydroxybenzotriazole hydrate (100 mg, 0.69 mmol), triethylamine (87 mg, 0.86 mmol) and CH2Cl2 (3 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11](Cl)=[N:10][CH:9]=2)[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:26]3[CH2:27][CH2:28][NH:23][CH2:24][CH:25]=3)=[N:10][CH:9]=2)=[O:15])[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]=[C:26]([C:11]2[CH:12]=[CH:13][C:8]([C:7](=[O:15])[NH:6][CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:9][N:10]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nc1
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: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)NCCC3CC3)cn2)CC1
Product: O=C(NCCC1CC1)c1ccc(C2=CCNCC2)nc1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a stirred solution of 6-chloronicotinic acid (2-cyclopropylethyl)amide (0.650 g, 2.893 mmol) in DMF (15 mL) was added 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.075 g, 3.479 mmol), potassium carbonate (1.202 g, 8.697 mmol) and tetrakis(triphenylphosphine)palladium (0.347 g, 0.300 mmol). The resulting mixture was heated to 80° C. for 24 hours and then filtered. Ethyl acetate (40.0 mL) was added to the mixture and the organic solution was washed with water (20 mL), saturated NaCl (20 mL), dried over MgSO4 and then concentrated in vacuo. The crude product was purified by column chromatography to yield the desired product, 5-(2-cyclopropylethylcarbamoyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.453 g, 42%).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[OH:39])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:40])[C@@H:7]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[C@@H:45]([N:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH2:6][CH2:5][CH2:4]1.[P:52](Cl)([O:57]CC)([O:54][CH2:55][CH3:56])=[S:53].C1(C)C=CC=CC=1.CCOC(C)=O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:55]([O:54][P:52]([O-:57])([O:47][CH2:46][CH3:48])=[S:53])[CH3:56].[CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[OH:39])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:40])[C@@H:7]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[C@@H:45]([N:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOP(=S)(Cl)OCC
Agent: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](N(C)C)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@@H](C=C[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]5O)C[C@@H]34)[C@@H]2CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOP([O-])(=S)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound Spinosyn H (261 mg, 0.364 mmol) was dissolved in dry pyridine (3 ml). DMAP (60 mg) was added, followed by diethyl chlorothiophosphate (152 mg, 125 μl, 0.80 mmol). The reaction mixture was stirred at RT under nitrogen. After 12 hrs. toluene (50 ml) and EtOAc (50 ml) were added. The solution was extracted with brine, then with 5% aq. NaHCO3. The organic layer was dried over and Na2SO4 and concentrated in vacuo. The residue was purified over a flash SiO2 column (30 g/EtOAc) to give compound 2'R)-(diethyl)thiophosphate of Spinosyn H; 84 mg, 27%) CI MS m/z 870 (M+1); 1H-NMR (CDCl3) δ 6.74 (1H, bs), 4.80 (1H, m), 4.22 (4H, 2× CH2, m), 1.30 (6H, 2× CH3, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2OCC[O:16]2)=[CH:7][CH:6]=1.Cl>C1COCC1.C(OCC)C>[CH:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1)=[O:16]
Reactant: OCCCc1ccc(C2OCCO2)c2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(CCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
To a solution of 2-[4-(3-hydroxypropyl)naphthyl]dioxolane (67 mg, 0.26 mmol) in anhydrous THF (5 mL) was added 1 N hydrochloric acid (1 mL). The mixture was stirred at room temperature for 48 hr, diluted with ethyl ether (20 mL), washed with satd. NaHCO3 solution (2×10 mL), dried (MgSO4), concentrated and coevaporated with CHCl3 (3×10 mL) to yield 40 mg (72%) of a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:20][N+:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:23]([F:35])[CH:22]=1.[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[C:37]#[CH:38]>C1COCC1>[C:31]([O:30][C:28]([NH:27][C:24]1[CH:25]=[CH:26][N:21]2[N:20]=[CH:38][C:37]([C:36]([O:40][CH2:41][CH3:42])=[O:39])=[C:22]2[C:23]=1[F:35])=[O:29])([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1cc[n+](N)cc1F
Reactant: C#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2ccc(NC(=O)OC(C)(C)C)c(F)c12
Reaction time: 0.5 h

Procedure:
K2CO3 (36.96 g, 267 mmol) was added to a solution of 1-amino-4-((tert-butoxycarbonyl)amino)-3-fluoropyridin-1-ium 2,4-dinitrophenolate (50 g, 121 mmol) in THF (500 mL) at 28° C. and continued stirring at same temperature for 30 min. Ethyl propiolate (14.3 g, 145 mmol) was added to above solution and stirring was continued at 28° C. for 16 hr. Reaction mixture was filtered to remove the salt, filtrate collected was diluted with EtOAc washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude obtained was purified by column purification (using 60-120 silicagel and 10% EtOAc in Hexane as eluant) to afford the title compound.
Reaction SMILES: [F:1][B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([N+]#N)=[CH:11]2.C(OCC)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=2
Reactant: F[B-](F)(F)F
Reactant: COc1ccc2ncc([N+]#N)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(F)cc2c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A suspension of 1007 g of 6-methoxy-3-quinolinediazonium fluoroborate taken in 9 l of toluene is heated to 60° C. in 85 minutes. A release of gas is observed at 60° C. The reaction medium is then gradually heated further for 90 minutes to 70-72° C. After having been kept at 72° C. for 90 minutes, the medium is then gradually heated again to 85° C. After cooling and stirring overnight, 4 l of ice-cold water are added to the suspension. After having stirred for 15 minutes, 2.5 l of ethyl acetate are added. After having stirred for 45 minutes, the pH is adjusted to pH=7-7.5 by adding 47% sodium hydroxide (250 ml). The medium is stirred for 30 minutes and then separated by settling out for 1 hour. The lower aqueous phase is re-extracted with ethyl acetate. The organic phases are combined together and washed with water. The solution is filtered and then concentrated under reduced pressure so as to give 655 g of crude 3-fluoro-6-methoxyquinoline. The crude product is distilled under reduced pressure. The distillation fractions (bp 103-110° C. under 1 mbar) containing the expected product are combined together. 498.9 g of 3-fluoro-6-methoxyquinoline (76%) are thus obtained in the form of a white solid which melts at 51-53° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:19](Cl)([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>ClCCl>[CH3:12][O:11][C:10]1[C:2]([NH:1][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(C(=O)O)c1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
2-amino-3-methoxybenzoic acid 97 (1 g, 6.0 mmol) and pyridine (0.97 mL, 12.0 mmol) were dissolved in dry dichloromethane (30 mL). The resulting mixture was cooled and Troc-Cl (0.9 mL, 6.6 mmol) was added drop wise. The reaction mixture was allowed to stir overnight at room temperature, then washed with HCl (1N, 50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over MgSO4 and evaporated to yield 1.42 g of crude product, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[O:18]1[CH2:53][CH:19]1[CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH:50]1[O:52][CH2:51]1.[OH-:54].[K+]>CO>[OH:18][CH:19]([CH2:53][N:6]1[C:5](=[O:54])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH:50]([OH:52])[CH2:51][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9]
Reactant: [OH-]
Reactant: C(COCCOCCOCCOCCOCC1CO1)OCCOCCOCCOCCOCC1CO1
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Agent: [K+]
Solvent: CO
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O

Procedure:
5.8 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 5.3 g of nonaethylene glycol bis(2,3-epoxypropyl)ether and 0.1 g of potassium hydroxide were reacted in 100 ml of methanol, following substantially the same procedure as in Example 1. The desired Compound No. 169 was obtained in the form of a colourless, viscous liquid, having an Rf value of 0.38 on thin-layer chromatography on silica gel using a 2:1:0.03 by volume mixture of ethyl acetate, methanol and triethylamine as developing solvent.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][CH:3]2[S:9][CH:10]=[CH:11][CH:2]12.[Br-:12].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:12][CH2:7][C:6]([C:5]1[S:1][CH:2]2[CH:11]=[CH:10][S:9][CH:3]2[CH:4]=1)=[O:8]
Reactant: [Br-]
Reactant: CC(=O)C1=CC2SC=CC2S1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)C1=CC2SC=CC2S1
Reaction time: 1 h

Procedure:
1-(3a,6a-Dihydro-thieno[3,2-b]thiophen-2-yl)-ethanone (453 mg, 2.48 mmol) was dissolved in THF (12 mL) and phenyltrimethylammonium tribromide (932 mg, 2.48 mmol) was added. After stirring for 1 h, the suspension was filtered over CELITE. The filtrate was diluted with diethyl ether, then washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated to afford the title compound which was carried on without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][CH2:9][C:10](Br)=[O:11]>>[C:2]1([NH:1][C:10](=[O:11])[CH2:9][Br:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Br)CBr
Reactant: Nc1ccccc1
Product: O=C(CBr)Nc1ccccc1

Procedure:
Aniline and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[OH:6])=[N+]=[N-].C([OH:20])C>[Pd]>[C:10]([OH:17])(=[O:20])[CH3:11].[NH2:1][CH2:4][C@@H:5]([C:7]1[C:15]2[S:14][C:13](=[O:16])[NH:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[OH:6]
Reactant: CCO
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: [Pd]
Product: CC(=O)O
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reaction time: 48 h

Procedure:
5% Palladium on carbon type 87L paste (22 g) was added to 7-[(1R)-2-azido-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one (example 1, step c) (225 g) dissolved in ethanol (3 L). The reaction was stirred under hydrogen (3 bar) for 48 h. A further 10 g of the catalyst was added and hydrogenation continued for a further 5 days. The reaction mixture was filtered and the solid (product+catalyst) suspended in ethanol (2.5 L) then acetic acid (150 mL) was added and the whole stirred overnight. The mixture was filtered again to remove the palladium on carbon catalyst. The solution was evaporated to dryness and azeotroped with toluene (2×1 L). The solid was slurried in tetrahydrofuran (1 L) for 4 hours, filtered and dried at 40° C. in vacuo to give the subtitled compound. Yield 57 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[Na+].C(OCC)(=O)C>O>[Na+:25].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][S:21]([O-:24])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCc1cccc(OCc2ccccc2)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)([O-])Cc1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
5.80 g of methanesulfonic acid 3-benzyloxybenzyl ester and 5.21 g of sodium sulfite were dissolved in 50 ml of water and stirred at 90° C. for 5 hours. The mixture was allowed to cool to room temperature overnight, then 30 ml of ethyl acetate were added and the mixture was stirred in an ice bath for 1 hour. The precipitate was filtered off with suction, washed twice with 10 ml of ice-water and twice with 10 ml of ice-cold ethyl acetate, and dried in a vacuum drying cabinet at 40° C. overnight. This gave the product (2.37 g) with a molecular weight of 300.3 g/mol (C14H13O4S.Na); MS (ESI): m/e=296 (M−Na++H2O+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[C:31]([F:34])([F:33])[F:32].[F-].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:32][C:31]([F:34])([F:33])[C:19]([OH:20])([OH:21])[CH:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC(O)(C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C(F)(F)F
Reaction time: 4 h
Yield: 96 %

Procedure:
Methyl 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (147d, 2.5 g, 6.6 mmol) was dissolved in THF (15 mL, dried over 4 Å MS) under Argon atmosphere and cooled in an ice-bath. Trimethyl(trifluoromethyl)silane (1.18 mL, 8 mmol) was added followed by Caesium fluoride (100 mg, 0.66 mmol). The cooling bath was removed and the stirring was continued at r.t. for 4 h. A solution of tetrabutylammonium fluoride in THF (1M, 7 mL, 7 mmol) followed by water (4 mL) was then added and the mixture was stirred for additional 1 h and then partitioned between ethyl acetate and water. The organic phase was washed twice with water, then brine and evaporated to afford 1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropane-2,2-diol (2.74 g, 95%)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[CH:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[C:13]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([CH:39]([OH:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:7][N:6]=3)[N:17]=[CH:16][N:15]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(O)c3ccccc3)cn2)cc1

Procedure:
N-[6-{2-(5-Bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide and benzaldehyde are treated in the same manner as in Example 129 to give 4-tert-butyl-N-[6-{2-(5-(α-hydroxybenzyl)primidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]-benzenesulfonamide.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C@@H:16]1[C@@H:20]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:19][C@H:18]([O:30][CH3:31])[C@:17]1([CH3:33])[OH:32])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C.O>[CH2:34]([O:32][C@:17]1([CH3:33])[C@H:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:20]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:19][C@@H:18]1[O:30][CH3:31])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
1.2 g of sodium hydride was added to an N,N-dimethylformamide solution of 7.2 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol, and thereafter, 5.1 g of benzyl bromide was added dropwise to the mixture at a temperature of 15° C. or lower. The obtained mixture was stirred at room temperature for 1.5 hours. Thereafter, 200 mL of water and 200 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with 200 mL of 1 mol/L hydrochloric acid and 200 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure, so as to obtain 9.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolane in the form of a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccnc1
Yield: 75.3 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2 g, 11.9 mmol) (Alfa) was reacted with nicotinaldehyde (1.13 mL, 11.9 mmol) (Aldrich) and piperidine (1.18 mL, 11.9 mmol) in methanol to give E/Z-6-chloro-3-pyridin-3-ylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 2.3 g, 75%)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:29][CH:26]4[CH2:27][CH2:28][S:23][CH2:24][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCSCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCSCC1
Yield: 84.4 %

Procedure:
A mixture 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 1.50 mmol) and tetrahydro-thiopyran-4-ylamine (0.19 g, 1.60 mmol) and DIEA (0.52 mL, 3.00 mmol) in IPA (4 mL) was heated in a microwave reactor at 120° C. for 10 minutes. The mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and then purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate/heptane) to afford (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(tetrahydro-thiopyran-4-yl)-amine (0.53 g, 86%). 1H NMR (400 MHz, CDCl3) δ 9.18-9.03 (m, 2H), 8.26-8.12 (m, 2H), 7.70-7.46 (m, 4H), 6.65 (d, J=4.2 Hz, 1H), 4.07-3.91 (m, 1H), 2.88-2.70 (m, 4H), 2.49-2.34 (m, 2H), 2.05-1.76 (m, 2H).