Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)=NN.IC1C=CC(N2CCC=C(N3CCOCC3)C2=O)=CC=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[C:43]3(N4CCOCC4)[C:44](=[O:55])[N:45]([C:48]4[CH:53]=[CH:52][C:51]([I:54])=[CH:50][CH:49]=4)[CH2:46][CH2:47][CH:42]3[C:41]([S:62]([CH3:65])(=[O:64])=[O:63])=[N:40]2)[CH:36]=[CH:37][CH:38]=1>C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[C:43]3[C:44](=[O:55])[N:45]([C:48]4[CH:49]=[CH:50][C:51]([I:54])=[CH:52][CH:53]=4)[CH2:46][CH2:47][C:42]=3[C:41]([S:62]([CH3:65])(=[O:64])=[O:63])=[N:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: CS(=O)(=O)C1=NN(c2cccc(Cl)c2)C2(N3CCOCC3)C(=O)N(c3ccc(I)cc3)CCC12
Agent: NN=CCl
Agent: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 70 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
The methanehydrazonoyl chloride (8.47 g, 31.7 mmol) and 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (12.17 g, 31.7 mmol) were combined in anhydrous toluene. The solution heated to 70° C. and triethylamine (13.2 mL, 95.1 mmol) was added dropwise. After the addition was complete the reaction was warmed to 90° C. and stirred at this temperature for 14 h. Analysis by LC/MS indicated formation of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-7a-morpholin-4-yl-1,3a,4,5,6,7a-hexahydro-pyrazolo[3,4-c]pyridin-7-one complete with less than 5% of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one remaining. The solvent was removed in vacuo. To the viscous oil was added dichloromethane (50 mL) then trifluoroacetic acid (30 mL) and heated to reflux for 4 h. The solvent was evaporated and the residue purified by flash column chromatography eluting with a gradient of hexane to 40% ethylacetate/hexane to give 10.65 g (64%) of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH3:5].[NH2-].[Li+].[CH3:8][O:9][C:10]([CH3:16])([O:12]CC#C)[CH3:11].BrCC>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:1][C:2]#[C:3][CH2:4][CH3:5])[CH3:11]
Reactant: C=CC=CC
Reactant: C#CCOC(C)(C)OC
Agent: [Li+]
Agent: [NH2-]
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 101.9 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 20 minutes to 100 ml (4 mol) of liquid ammonia at −37° C. The mixture was stirred until no more lithium floated (after approximately 15 minutes). A dark cyan solution of lithium in liquid ammonia was obtained. 6.34 g (92 mmol) of piperylene (=1,3-pentadiene) were added portion wise within 30 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 10.1 g (71 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (89.7% GC) were added with a dropping funnel to the reaction mixture at −37° C. within 30 minutes. The reaction mixture was held at −37° C. for about 1 hour. 14.0 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 30 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. 50 ml of water were added to the reaction mixture at 22° C., and the mixture was vigorously stirred until all salt was dissolved. The water layer was extracted once with 50 ml of n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. 11.3 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 87.5% (yield 85.3% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[CH2:19][CH:20]4[NH:24][CH:23]([C:5]=3[C:4]=2[C:3]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]4.[C:32]1([S:38](C2C=CC=CC=2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([S:38]([C:2]2[CH:10]=[CH:9][C:8]3[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[CH2:19][CH:20]5[NH:24][CH:23]([C:5]=4[C:4]=3[C:3]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]5)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1c(Br)ccc2c1c1c(n2COCC[Si](C)(C)C)CC2CCC1N2
Product: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2COCC[Si](C)(C)C)CC2CCC1N2
Yield: 58 %

Procedure:
The product of step A was converted to the phenyl sulfone derivative following the procedure of example 1, step C. The crude material was purified by flash column chromatography (SiO2 98:2 to 65:35 hexane/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-5-[(trimethylsilyl)ethoxy]methyl-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole-carboxylate (1.30 g, 58%) as a brown foam: 1H NMR (CDCl3, 300 MHz) δ 8.28 (s, 1H), 8.03-8.09 (m, 2H), 7.75-7.83 (m, 1H), 7.51-7.62 (m, 4H), 5.28-5.49 (m, 3H), 4.66-4.89 (m, 1H), 3.45-3.68 (m, 3H), 2.64 (d, J=16.2 Hz, 1H), 2.45-2.52 (m, 1H), 2.25-2.38 (m, 1H), 2.01-2.11 (m, 1H), 1.64-1.75 (m, 1H), 1.46 (br s, 9H), 0.88-0.95 (m, 2H), −0.11 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][Cl:29])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[ClH:29].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(OC)cc1)C(C)C
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C(C)C)N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2(R)-[[4-methoxybenzenesulfonyl]amino]-3-methylbutanoate (1662 g, 5.52 mol) in dimethylformamide (10.9 L) is added 3-picolyl chloride hydrochloride (947.3 g, 5.77 mol) followed by powdered potassium carbonate (2409.9 g, 17.36 mol). The reaction mixture is stirred at room temperature for 2 days. At that time, additional quantities of 3-picolyl chloride hydrochloride (95 g) and powdered potassium carbonate (241 g) are added, and the reaction is stirred for 3 more days. The solids are then filtered away, the crude product is poured into water (22 L), and the pH is adjusted to pH=8 with 6N sodium hydroxide. This solution is extracted well with toluene (4×10 L), the combined organic layers are washed with water (2×12 L), and then with 6N hydrochloric acid (3×1600 mL). This aqueous layer is then re-adjusted to pH=8 with 6N sodium hydroxide, extracted with toluene (4×10 L), dried (Na2SO4), and the solvent is evaporated. The oil obtained is re-dissolved in ethyl acetate (12 L), cooled to 5° C., and to this is added methanolic HCl (834 mL). After stirring for 2 hours, the precipitated product is collected by filtration to give methyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-3-methylbutanoate hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]#[N:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([NH2:15])=[O:18])[O:10][N:9]=2)=[O:7])=[CH:16][CH:17]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1nc(C(=O)c2ccc(F)cc2)no1
Product: NC(=O)Cc1nc(C(=O)c2ccc(F)cc2)no1
Temperature: 0 °C
Yield: 96 %

Procedure:
A solution of [3-(4-fluorobenzoyl)-1,2,4-oxadiazol-5-yl]acetonitrile (5.0 g) in 98% H2SO4 (50 ml) was stirred at room temperature for 3 hours. The resulting solution was added slowly to a liter of ice water with mechanical stirring. The precipitated solid was collected by filtration and washed with water (5×300 ml) and cold isopropanol (3×150 ml). The amide was dried in vacuum to yield 5.2 g (96%) of a powder, m.p. 197°-199°.
Reaction SMILES: ClC1C=C(N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])C=C(Cl)C=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[NH2:20].C(#N)CC#N.O.[NH2:31][NH2:32]>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][N:10]=[C:11]2[C:12]([NH2:13])=[N:32][N:31]=[C:14]2[NH2:15])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cc(Cl)cc(Cl)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cc(Cl)cc(Cl)c1

Procedure:
4-[(3,5-dichlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 120 mg (0.5 mmol) of 2-[(3,5-dichlorophenyl)hydrazono]malononitrile, which was derived from 3,5-dichloroaniline (162 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 25 mg (18%) of the compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:19][NH:20][S:21]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:23])=[O:22]>C(O)CC(C)C.C(O)C>[ClH:1].[CH3:19][NH:20][S:21]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:2]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:27][CH:26]=1)(=[O:22])=[O:23]
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Reactant: Clc1nc(Nc2ccccc2)c2ccccc2n1
Solvent: CCO
Solvent: CC(C)CCO
Product: CNS(=O)(=O)Cc1ccc(Nc2nc(Nc3ccccc3)c3ccccc3n2)cc1
Product: Cl
Temperature: 170 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-chloro-4-phenylamino-quinazoline (0.92 g) (prepared as described in Example 1a and N-methyl-(4-aminophenyl)-methanesulfonamide (0.80 g) in 10 ml of isopentylalcohol is stirred under nitrogen at 170° C. for 15 min in a sealed vessel. The warm reaction mixture is diluted with 10 ml ethanol and the hydrochloride salt, which is crystallizing on cooling, is filtered off to yield N-methyl-[4-(4-phenylamino-quinazolin-2-ylamino)-phenyl]-methanesulfonamide hydrochloride as light yellow crystals melting at 259-263° C.; Rf (A2) 0.11, FAB-MS: (M+H)+=420. Analytical data: C22H21N5O2S+HCl.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=3)[CH:17]=1)[N:5]=2)=[O:36]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.451 mmol) produced in Example C33(iv) in N,N-dimethylformamide (4.0 mL) was added chloroacetyl chloride (50 μL, 0.631 mmol), and the mixture was stirred at room temperature for 2 hr. Chloroacetyl chloride (25 μL, 0.314 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:53]=[CH:52][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]4[CH2:47][CH2:46][CH:45]([C:48]([OH:51])([CH3:50])[CH3:49])[CH2:44][CH2:43]4)=[CH:37][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]3[CH:27]4[CH2:28][CH2:29][CH:23]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26]4)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[ClH:54].O1CCOCC1>C(Cl)Cl>[ClH:54].[ClH:54].[CH:23]12[N:22]([C:20]([C@@H:17]3[CH2:18][CH2:19][C@H:14]([N:13]4[C:12]5[CH:37]=[C:38]([CH2:41][N:42]6[CH2:43][CH2:44][CH:45]([C:48]([OH:51])([CH3:50])[CH3:49])[CH2:46][CH2:47]6)[CH:39]=[CH:40][C:11]=5[NH:10]/[C:9]/4=[N:8]\[C:6](=[O:7])[C:5]4[CH:52]=[CH:53][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:15][CH2:16]3)=[O:21])[CH:27]([CH2:28][CH2:29]1)[CH2:26][NH:25][CH2:24]2
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2C(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)N5C6CCC5CNC6)CC4)c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 8-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (70 mg, 0.096 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (0.120 mL, 0.479 mmol). The suspension was stirred overnight at RT. After 16 hours, the reaction was concentrated to provide (E)-N-(1-(cis-4-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide dihydrochloride as a white powder (68 mg, 101% yield). MS, m/z (C36H47FN6O3.2HCl): calcd, 630.4. found, 631.2 [M+H].
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[S:14][C:13]([NH2:16])=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1COCC1.ClCCl>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:16][C:13]2[S:14][C:15]3[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=3[N:12]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(C2CCCCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 0.1 g (0.38 mMol) 7-cyclohexyl-4-methoxy-benzothiazol-2-ylamine in 3 ml THF were added 0.2 ml ethyl diisopropyl amine and 0.0865 g (0.46 mMol) 4-chloromethyl-benzoyl chloride, dissolved in 1 ml of dichloro methane. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated to dryness, the residue taken up in dichloro methane and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was triturated in ethyl ether, filtered and dried to yield 0.11 g (68%) of 4-chloromethyl-N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-benzamide as a light yellow foam. ES-MS m/e (%): 415 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22](O)[CH3:23]>ClC(Cl)C.C(N)CC1C=CC=CC=1>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:7][CH2:6][CH2:5][C:23]3[CH:22]=[CH:4][CH:3]=[CH:2][CH:21]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCO
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Agent: NCCc1ccccc1
Solvent: CC(Cl)Cl
Product: O[C@H](CNCCc1ccccc1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, phenethylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS=˜88%, [M+H]+=407.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([OH:16])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:17]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOC(=O)c1c(O)cccc1CC=C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCOC(=O)c1c(CC=C)cccc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 98 %

Procedure:
To a solution of allyl 6-allyl-2-hydroxybenzoate (v) (1.2 g, 5.5 mmol) in acetone (12 mL) was added K2CO3 (0.84 g, 6.05 mmol) and MeI (1.04 mL, 16.5 mmol) and the mixture was stirred for 40 h at rt. After filtration of the mixture through a short plug of silicagel, the filtrate was concentrated in vacuo and the residue purified by 1FC (3% Et2O/pentane) to give 1.25 of allyl 6-allyl-2-methoxybenzoate (via) (98%) as a colorless oil. via: IR 2918, 2850, 1733, 1715, 1585, 1363, 1244, 1223, 914, 733 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29 (1H, app.t, J=8.0 Hz), 6.83 (1H, d, J=7.6 Hz), 6.79 (1H, d, J=8.4 Hz), 5.97-6.06 (1H, m), 5.86-5.96 (1H, m), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.4 Hz), 5.0 (1H, br d, J=16.8 Hz), 5.04 (1H, br d, J=10.0 Hz), 4.82 (2H, br d, J=6.0 Hz), 3.82 (3H, s), 3.36 (2H, d, J=6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 167.8, 156.6, 138.7, 136.4, 132.1, 130.6, 123.6, 121.8, 118.8, 116.5, 109.2, 66.0, 56.1, 37.9; MS (EI) 232 (M+, 18), 191 (28), 175 (34), (147 (50), 132 (100), 115 (58). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.10; (MOM): IR 2956, 2928, 2853, 1732, 1636, 1589, 1466, 1256, 1153, 1031, 919 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26 (1H, dd, J=7.6, 8.4 Hz), 7.01 (1H, d, J=7.6 Hz), 6.88 (1H, d, J=Hz), 6.01 (1H, ddt, J=5.6, 10.0, 17.2 Hz), 5.90 (1H, ddt, J=6.8, 10.4, 16.8 Hz), 5.42 (1H, br d, J=17.2 Hz), 5.28 (1H, br d, J=10.0 Hz), 5.17 (2H, s), 5.06 (1H, br d, J=16.8 Hz), 5.05 (1H, br d, J=10.4 Hz), 4.81 (2H, d, J=5.6 Hz), 3.46 (3H, s), 3.37 (2H, d, J=6.8 Hz), 13C NMR (75 MHz, CDCl3) 8167.8, 154.2, 138.8, 136.5, 132.2, 130.7, 124.7, 123.0, 118.9, 116.6, 112.9, 94.9, 66.0, 56.4, 37.8. HRMS Calcd for C15H804Li (MLi+): 269.1365. Found: 269.1371.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:11]([Sn:15]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16]I)[CH2:12][CH2:13][CH3:14].CN(C)C=O>O1CCCC1.O>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][CH2:16][Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4]1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 73.1 %

Procedure:
To a solution of 4-hydroxy-1-methylpiperidine (802 mg, 6.96 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (50%, 334 mg, 6.96 mmol) at room temperature, and the mixture was stirred at room temperature for 35 minutes. To the reaction mixture were added a solution of tributyl-iodomethyl-tin (2.00 g, 4.64 mmol) in tetrahydrofuran (5 ml), and N,N-dimethylformamide (10 ml) at room temperature, and the mixture was stirred at room temperature for 7 hours and 50 minutes. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=100:1 to 20:1) to obtain the title compound (1.42 g, 3.39 mmol, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12](OCC)(OCC)OCC.[N-:22]=[N+:23]=[N-:24].[Na+]>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH:12]=[N:24][N:23]=[N:22]1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(-n2cnnn2)c1

Procedure:
3-Aminophenylacetic acid (1.0 g, 6.62 mmol) was stirred in acetic acid (15 ml) and added triethyl orthoformate (2.203 ml, 13.23 mmol) followed by sodium azide (0.774 g, 11.91 mmol) then heated to reflux for 3 hrs. The reaction was concentrated and added water then extracted with ethyl acetate and tetrahydrofuran (2×). The organic layers were combined and washed with brine (1×), then dried over Na2SO4 and evaporated to dryness. The residue was triturated with ether, filtered and dried to yield [3-(1H-tetrazol-1yl)phenyl]acetic acid. LC-MS (IE, m/z): 205 [M+1]+; 1H-NMR (500 MHz, DMSO) δ ppm 12.45 (b, 1H), 10.1 (s, 1H), 7.84 (s, 1H), 7.79 (dd, J=8 Hz, 1.4 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 3.73 (s, 2H);
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:19]1[N:23]2[N:24]=[CH:25][C:26]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:27][C:22]2=[N:21][CH:20]=1>Cl>[F:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11]([C:19]3[N:23]4[N:24]=[CH:25][C:26]([C:28]([OH:31])([CH3:29])[CH3:30])=[N:27][C:22]4=[N:21][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1cccc(-c2ncc(F)cc2F)c1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Agent: Cl
Product: CC(C)(O)c1cnn2c(-c3cccc(-c4ncc(F)cc4F)c3)cnc2n1
Temperature: 0 °C

Procedure:
3-(3,5-Difluoropyridin-2-yl)phenylboronic acid (25 mg, 0.11 mmol) was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (27 mg, 0.11 mmol) using the method of Example 20. Purification by chromatography (silica gel, 3% MeOH/CH2Cl2) gave impure product as a yellow solid. The product was then dissolved in hydrochloric acid (2 N, 50 ml), filtered and washed with diethyl ether (2×20 ml). The acid solution was cooled to 0° C. and neutralised with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated to give the title compound as a yellow solid: 1H. NMR (400 MHz, CDCl3) δ 1.72 (6H, s), 3.35 (1H, s), 7.32-7.38 (1H, m), 7.64 (1H, t, J 8 Hz), 7.95-7.98 (1H, m), 8.10-8.13 (1H, m), 8.33 (1H, 8), 8.48 (1H, d, J 3 Hz), 8.60-8.61 (1H, m), 8.79 (1H, s); MS (ES+) m/z 368 [M+H]+.