Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH2:33](O)[CH2:34][OH:35].C(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:35][CH2:34][CH2:33][O:23]3)[CH2:13][CH2:12]4)[C@H:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: COC(OC)OC
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@H]12

Procedure:
A solution of 63.9 g of 3-acetoxy-7α-(5-acetoxypentyl)-estra-1,3,5(10)-trien-17-one in 460 ml of dichloromethane is stirred with 460 ml of ethylene glycol, 155 ml of trimethyl orthoformate and 1.2 g of para-toluenesulfonic acid for 3 hours at a bath temperature of 50° C. Then, it is diluted with dichloromethane, washed with sodium bicarbonate and common salt solution and dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 63.2 g of 3-acetoxy-7α-(5-acetoxypentyl)-17,17-ethylenedioxy-estra-1,3,5(10)-triene is obtained as oil.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=O)C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]

Procedure:
6.0 G. of 1-acetamido-2-nitro-4-phenoxybenzene and 20 ml. sodium hydroxide in methanol is warmed gently until homogeneous, diluted with water and ice, and the methanol evaporated to give 1-amino-2-nitro-4-phenoxybenzene.
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[NH:11]1[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]1=[O:13]>N1C=CC=CC=1>[CH:17]1[C:15]([NH2:16])=[N:14][C:12](=[O:13])[N:11]([C@@H:2]2[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]2[OH:4])[CH:18]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: c1ccncc1
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
M-PEOZ-O—CH2—CO2—NHS (M-PEOZ-SCM 5000) (180 mg, 0.034 mmol) was dissolved in 11 mL of pyridine and added to a solution of cytosine arabinose (Ara-C) (5.7 mg, 0.023 mmol), previously dissolved in 5 mL of anhydrous pyridine at 0° C. The resulting solution stirred for 72 hours at room temperature. Reverse phase HPLC (C-18 column) showed that reaction was complete. After evaporation of the solvent, the product was dissolved in methylene chloride (5 mL) and added drop by drop into 150 mL ether. The precipitate was collected by centrifugation at 4° C. and dried under vacuum. Yield 150 mg, 80%. NMR showed the usual peaks of the M-PEOZ backbone (above) plus the pyrimidine protons of Ara-C at 7.31, 7.67, 8.16, and 8.62 ppm. Exposure of the conjugate to pH 8 buffer showed that Ara-C is slowly released (15% after 24 hours), so the conjugate can be regarded as a prodrug.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:6]2=[CH:5][CH:4]=1.[CH2:15](O)[CH3:16]>>[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:6]2=[CH:5][CH:4]=1
Reactant: O=C(O)c1cc2ccc(Cl)nc2[nH]1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc2ccc(Cl)nc2[nH]1
Yield: 25 %

Procedure:
HCl gas is bubbled through a solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (36 g, 183 mmol) in ethanol (500 mL) at 0° C. for 30 min. The reaction mixture is then heated at reflux for 16 h. The solvent is evaporated and the residue is diluted with CH2Cl2 and filtered. The filtrate is evaporated and the residue is washed with diethyl ether (2×250 mL). The organic layers are dried (Na2SO4) and concentrated. The crude residue is purified by passing through the column of neutral alumina, eluting with 10% EtOAc/hexane to afford the title compound as a white solid (10 g, 25%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=2.C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:25]1([CH2:31][C:32]([O:1][C:2]2[C:3]3[C:8]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[O:12][CH3:13])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=3)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc2c(c(O)c1OC)=NC(=O)C(=O)N=2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(c(OC(=O)Cc3ccccc3)c1OC)=NC(=O)C(=O)N=2
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a suspension of 5-hydroxy-6,7-dimethoxy-2,3-quinoxalinedione (48) (50 mg, 0.22 mmol) in 3 mL of methylene dichloride was added 0.14 mL of triethylamine and phenylacetyl chloride (77.5 mg, 0.5 mmol, Aldrich) at 0° C. The resulting mixture was stirred at room temperature for 12 hr. The reaction mixture was then poured into ice-water (5 g). A white solid precipitated and was collected by suction filtration, washed with water (3×5 mL) and ethyl acetate (3×2 mL), and dried in vacuo, giving 60 mg (77%) of the product as a white solid; mp 298°-300° C.; 1H NMR (DMSO-d6, 300 MHz) δ3.405 (s, 3H), 3.728 (s, 3H), 4.024 (s, 2H), 6.653 (s, 1H), 7.359 (m, 5H), 11.773 (s, 1H), 11.846 (s, 1H). EIMS m/e 356 (25, M+), 238 (100). (HPLC 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([C:18]([N:15]3[CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13][CH2:14]3)=[O:19])[N:9]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2nn[nH]c2c1
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)n2nnc3ncc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Chloro-1H-[1,2,3]triazolo[4,5-b]pyridine (200 mg, 1.29 mmol) and 4-methyl-piperidin-1-carbonyl chloride (418 mg, 2.56 mmol) were dissolved in 10 ml of pyridine. Then triethylamine (180 μl, 3.88 mmol) was added and stirred at room temperature for 4 h and left to stand overnight. The reaction mixture was concentrated and the residue was mixed with water and ethyl acetate. The organic phase was separated off, the aqueous phase was extracted once more, and the combined organic phases were washed with water and concentrated. The crude product was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 106 mg (29%) of (6-chloro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-(4-methyl-piperidin-1-yl)-methanone, M+H+: 280.2.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17](/[C:20](=[CH:6]\[C:5]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])/[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)/C(=C/c1ccc(Cl)cc1[N+](=O)[O-])c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A 2 L flask equipped with a mechanical stirrer was charged with 183 g of 2-nitro-4-chlorobenzaldehyde, 212 g of 4-bromophenylacetic acid and 233 mL of acetic anhydride. To this solution was added 82 g of potassium carbonate and the reaction was stirred overnight at 100° C. The resulting dark mixture was cooled down to room temperature and 1.6 L of water was added followed by 800 mL of 10% HCl. The solution was decanted and taken up in water/ethyl acetate. Layers were separated, organic phase was washed with brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. The residue was triturated in EtOH and the mother liquor was triturated 4 more times with EtOH to afford 219 g of the desired (2E)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid.
Reaction SMILES: [Cl-].[NH4+].[CH:3]1[C:20]2[C:19]3[C:10](=[C:11]([C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:22])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[N:18]=3)[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C.C(OCC)(=O)C.[Zn]>[CH:3]1[C:20]2[C:19]3[NH:18][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]([C:21]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:22])[C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Oc1ccccc1)c1c2ccccc2nc2c1ccc1ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Oc1ccccc1)C1c2ccccc2Nc2c1ccc1ccccc21
Reaction time: 2 h

Procedure:
Ammonium chloride (10 g) and 10 g of zinc were added to an Ar-purged suspension of 1.0 g of the ester from step (b) in ethanol. The mixture was stirred for 2 h, filtered and the solids washed with CH2Cl2. The combined solutions were evaporated to dryness producing a white solid which was dissolved in ethyl acetate and washed with 3×25 mL of water. The product was purified by chromatography using 10% ethyl acetate/hexane. 1H NMR (CDCl3) δ 5.48 (s, 1H), 5.69-7.27 (m, 9H), 7.41-7.55 (m, 5H), 7.83-7.88 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.BrN1C(=[O:22])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:22])=[CH:4][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: C[N+]1([O-])CCOCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 8.5 %

Procedure:
Combine 4-fluoro-1-methyl-3-phenoxybenzene (2.43 g, 12.0 mmol), N-bromosuccinimide (4.92 g, 27.6 mmol), benzoyl peroxide (408 mg, 1.68 mmol), and carbon tetrachloride (55 mL). Heat the mixture at reflux temperature for 6.5 h and cool to 0° C. for 64 h. Filter the solids and concentrate the filtrate. Dissolve the residue in chloroform and wash with ice cold sodium carbonate solution. Dry the chloroform solution over sodium sulfate, filter and concentrate under reduced pressure. Dissolve the residue in acetonitrile (50 mL) and add 4-methylmorpholine-4-oxide (4.6 g, 39.1 mmol) and powdered 4 Å sieves (200 mg). Stir at ambient temperature for 20 h, filter and concentrate. Purify by silica gel chromatography (5%, 30% ethyl acetate/hexanes) to give 220 mg (8%) of the title compound: MS (m/e): 216 (M+).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1>CN(C=O)C.C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[CH:11]=[CH:10][C:9]=1[C:15]1[S:19][C:18]([N:20]([CH3:31])[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:17][N:16]=1
Reactant: c1cn[nH]c1
Reactant: CN(c1nnc(-c2ccc(F)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(c1nnc(-c2ccc(-n3cccn3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Cs2CO3 (128 mg, 0.392 mmol) was added to a stirred solution of 5-(2-chloro-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (50 mg, 0.131 mmol) and 1H-pyrazole (13 mg, 0.196 mmol) in DMF (1.3 mL). The reaction mixture was stirred at room temperature for 4 days then warmed to 60° C. and stirred for an additional 18 hours. The reaction mixture was diluted with DCM (10 mL), filtered through celite, and the DCM was removed in vacuo to afford the crude product as a pale brown liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified), collecting at 324 nm. The product containing fractions were combined and loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (10 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the title compound as a clear glass-like solid (37 mg, 66% yield). LC-MS: Rt 0.97 min; MS m/z 431.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (d, J=2.53 Hz, 1H), 8.14 (dd, J=5.56, 3.03 Hz, 2H), 7.97-8.02 (m, 1H), 7.83 (d, J=1.52 Hz, 1H), 6.64-6.60 (m, 1H), 4.37 (tt, J=12.25, 3.16 Hz, 1H), 3.02 (s, 3H), 1.63 (dd, J=12.13, 3.03 Hz, 2H), 1.45 (t, J=12.13 Hz, 2H), 1.21 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1.Br[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([NH2:46])[CH:40]=[CH:39]2.CCO>C(Cl)Cl.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>[NH2:46][C:41]1[CH:40]=[CH:39][C:38]2[C:43](=[CH:44][CH:45]=[C:36]([C:11]3[CH:12]=[C:13]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)(=[O:16])=[O:17])[C:8]([Cl:7])=[N:9][CH:10]=3)[CH:37]=2)[N:42]=1
Reactant: Nc1ccc2cc(Br)ccc2n1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2Cl)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: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(N)ccc4c3)cnc2Cl)cc1
Temperature: 90 °C
Yield: 11.6 %

Procedure:
A reaction tube was charged with sodium carbonate (353 μl, 706 μmol), Pd(Ph3P)4 (16 mg, 14 μmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (100 mg, 235 μmol), 6-bromoquinolin-2-amine (53 mg, 235 μmol) and 1.2 mL EtOH. The tube was sealed and the mixture was heated at 90° C. for 2 h. The mixture was diluted with CH2Cl2 and washed with water. The organic portion was dried with MgSO4, filtered and concentrated. The crude material was dissolved in MeOH/DMSO and purified by reverse phase chromatography, 10-90% ACN/0.1% TFA in water over 15 min. The aqueous portion was brought to ˜pH 7 and extracted. The organic portion was dried, filtered and concentrated to provide N-(5-(2-aminoquinolin-6-yl)-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (12 mg, 12% yield) as a light yellow solid. MS (ESI pos. ion) m/z calc'd for C21H17ClN4O3S: 440.9/442.9; found 441.0/443.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H), 6.88 (br s, 2 H), 6.89 (d, 1 H, J=8), 7.15-7.18 (m, 2 H), 7.61 (d, 1 H, J=8), 7.75-7.80 (m, 3 H), 7.97-8.00 (m, 2 H), 8.03-8.06 (m, 1 H), 8.62-8.63 (m, 1 H), 10.46 (br, s, 1 H).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][C@@H:9]([CH2:11][OH:12])[C@@H:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:7]1)(=O)=O.CN(C)C=O.[N-:26]=[N+:27]=[N-:28].[Na+]>>[N:26]([C@@H:6]1[CH2:10][C@@H:9]([CH2:11][OH:12])[C@@H:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N=[N+]=[N-])C[C@H]1CO
Temperature: 55 °C

Procedure:
To a solution of (1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-(hydroxymethyl)-cyclopentyl methanesulfonate (0.470 g, 0.00145 mol) in N,N-Dimethylformamide (6 mL, 0.08 mol) was added sodium azide (0.4 g, 0.006 mol) 23° C., and the mixture was heated at 55° C. for 3 hours. The reaction was cooled to 23° C., quenched by addition of water and extracted with EtO (3×), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (10 to 25% ethyl acetate/hexane) to obtain 211 mg (53.7%).
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].CS(O[CH2:11][C:12]([CH3:25])([CH3:24])[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([Br:22])=[C:17]([CH3:23])[CH:16]=1)(=O)=O>CN1CCCC1=O.C(OCC)C>[Br:22][C:18]1[C:17]([CH3:23])=[CH:16][C:15]([O:14][CH2:13][C:12]([CH3:25])([CH3:24])[CH2:11][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][C:19]=1[CH3:21]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(OCC(C)(C)COS(C)(=O)=O)cc(C)c1Br
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1cc(OCC(C)(C)CS(C)(=O)=O)cc(C)c1Br
Temperature: 180 °C

Procedure:
In a microwave vial sodium methanesulfinate (720 mg) is added to a solution of 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropyl methanesulfonate (271 mg) in N-methyl-2-pyrrolidinon (NMP) (8 mL). The mixture is heated to 180° C. for 30 minutes. Then the mixture is diluted with diethylether, washed with water and brine and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 32 mg; LC (method 8): tR=0.47 min; Mass spectrum (ESI+): m/z=349 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:13]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(N(c2ccccc2)c2ccccc2)c1

Procedure:
A solution of 2 g of 3-fluoro-4-nitroanisole in 16 ml of aniline was stirred for 24 hours at 140° C. After cooling, it was taken up in ethyl acetate and extracted with 2N aqueous hydrochloric acid. The organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[CH2:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.[Br:16]N1C(=O)CCC1=O>CN(C)C=O>[Br:16][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][C:9]([CH3:13])([CH3:14])[CH2:8][C:7]2=[O:15]
Reactant: COc1ccc2c(c1)OC(C)(C)CC2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-chroman-4-one (Compound 1, 5.81 g, 28.2 mmol) in anhydrous N,N-dimethylformamide (15 mL) under argon at 25° C. was added N-bromosuccinimide (5.02 g, 33.8 mmol). The mixture was stirred at ambient temperature for 12 h. The product was extracted with diethyl ether. The organic layers were washed with water, brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo and purified by column chromatography (silica gel, 5% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH:18]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-]>ClCCl>[CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:15])([F:16])[F:17])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH2:18])[CH2:4][C@H:3]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)OC(C)(C)C)c2nnc(C3(C(F)(F)F)CC3)n21
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2nnc(C3(C(F)(F)F)CC3)n21
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a solution of crude tert-butyl {(5R,6S,8S)-5-methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-yl}carbamate (136 mg, 0.31 mmol) in dichloromethane (3.1 mL) was added trifluoroacetic acid (721 μL, 9.4 mmol) and the resulting mixture stirred 30 min. Saturated aqueous bicarbonate was added, and the resulting mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse chromatography (C-18, 95% water/acetonitrile 25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (38 mg). MS 337.2 (M+1).
Reaction SMILES: I[C:2]1[C:3]([CH3:19])=[N:4][C:5]([NH2:18])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C=O)C.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>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[C:3]([CH3:19])[N:4]=[C:5]([NH2:18])[N:6]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1nc(N)nc(-c2ccc(S(C)(=O)=O)cc2)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2ccc(S(C)(=O)=O)cc2)c1C#C[Si](C)(C)C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 3.0 g (7.7 mmol) 5-iodo-4-methyl-6-(4-methanesulfonyl-phenyl)-pyrimidin-2-ylamine (A-33) and 1.6 mL (12 mmol) trimethylsilylethyne using 147 mg (0.77 mmol) CuI, 541 mg (0.77 mmol) PdCl2(PPh3)2 and 11 mL (7.7 mmol) triethylamine in 18 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica (DCM/MeOH gradient). Yield: 2.45 g (71%, approximately 80% pure).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:18])=O.O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](CO)COCc1ccccc1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](CBr)COCc1ccccc1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
Dissolve (R)-2-(benzyloxy-methyl)-3-methyl butanol (15.6 g, 75 mmol) in N,N-dimethyl formamide (246 ml), add phosphorus oxybromide (22.58 g, 78.75 mmol) in droplets slowly and control the temperature below 50° C. in that process, and then let them to react at 50° C. for 3 hours. Cool down to room temperature, and pour the reactant liquid into water (246 ml) slowly, extract with normal hexane for three cycles, combine the normal hexane layers, wash twice with saturated sodium bicarbonate and saturated sodium chloride respectively, dry the organic layer with anhydrous sodium sulfate, filter, and condense the filtrate so as to obtain 18.1 g of oily matter. Treat the oil matter by reduced pressure distillation to obtain 16.6 g of colorless transparent liquid; the yield is 81.1%, and the chiral purity is ≧99.9%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(aminomethyl)phenylamino]-1-phenyl-methylidene}-2-indolinone, N-tert.butoxycarbonyl-glycine, TBTU, HOBt and N-ethyl-N,N-diisopropylamine in DMF.