Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(OC(=O)C)C>C1COCC1.O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CNC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
1.316 g N-methylacetamide was dissolved in 60 mL THF. 2.02 g Potassium tert-butoxide was added and the mixture stirred for 20 min at 50° C. Then 3 g of 4-bromobenzylbromide dissolved in 10 mL THF was added and the mixture stirred for 2 h at 50° C. After cooling ethylacetate and water were added and the organic phase extracted with water (1×), dried and the solvent distilled off to yield 2.8 g N-(4-bromobenzyl)-N-methylacetamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:30].[Cs+].[Cs+].C[N+]([O-])(C)C.CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:14][C:13]([CH2:15][CH2:16][NH:17][C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[C:12]([CH:18]=[O:30])[C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CS(=O)(=O)c1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Reactant: O=C([O-])[O-]
Agent: C[N+](C)(C)[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(NCCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C=O)cc1
Yield: 24.1 %

Procedure:
A mixture of 3.0 g (7.28 mmol) of the compound of step A, above, 4.74 g (14.6 mmol) of Cs2CO3, 1.62 g (14.6 mmol) of trimethylamine N-oxide and 24 ml of dimethyl sulfoxide is stirred at 120° C. for 4 days. The reaction mixture is cooled and diluted with 400 ml of water producing a brown precipitate which is collected by filtration. The crude product is dissolved in methanol, filtered and evaporated onto silica gel. The coated silica gel is then added to a column and eluted with 10% methanol in chloroform to yield 0.75 g (24%) of title compound as an off white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[CH2:16]([S-:18])[CH3:17].[Na+]>CN(C=O)C.[Li+].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:16]([S:18][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2)[CH3:17]
Reactant: CC[S-]
Reactant: NS(=O)(=O)c1ccc2cccc(I)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCSc1cccc2ccc(S(N)(=O)=O)cc12
Temperature: 50 °C
Yield: 29.9 %

Procedure:
A solution of 8-iodonaphthalene-2-sulfonamide (Intermediate 7, 100 mg, 0.30 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.015 mmol) and sodium ethanethiolate (50 mg, 0.60 mmol) in DMF (2 mL) was purged with argon. The reaction mixture was heated to 50° C. for 12 h. Additional sodium ethanethiolate (25 mg, 0.30 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (240 mg, 0.30 mmol) were added, and the reaction mixture was heated at 125° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with 10% aq. LiCl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (24 mg, 30%). 1H NMR (CD3OD) δ 9.02-8.98 (m, 1H), 8.08-8.03 (m, 1H), 8.00-7.95 (m, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.73 (dd, J=7.4, 1.0 Hz, 1H), 7.64-7.57 (m, 1H), 3.09 (q, J=7.3 Hz, 2H), 1.34 (t, J=7.4 Hz, 3H); MS(ESI−) m/z 266.2 (M−H)−.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:22])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1C(OC(C)(C)C)=O)([O-:3])=[O:2].[ClH:23]>C(OCC)(=O)C>[ClH:23].[N+:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:22])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCCCO[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCCCO[N+](=O)[O-])[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cooled at 0° C. solution of N-Boc-L-proline 3-nitrooxypropyl ester (2.1 g, 6.6 mmol) in Ethyl acetate (50 mL) a 6.8 M solution of HCl in ethyl acetate (19.4 mL) was added and the solution was slowly warmed to room temperature and stirred for 5 hours. Then the solvent was evaporated affording L-proline 3-nitrooxypropyl ester hydrochloride (1.7 g, quantitative) as a foam.
Reaction SMILES: [F:1][CH:2]1[CH:7](O)[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].FC1C(OC(C)C)NC(=O)NC1=O>>[F:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][CH:7]=1
Reactant: O=C1NC(=O)C(F)C(O)N1
Agent: CC(C)OC1NC(=O)NC(=O)C1F
Product: O=c1[nH]cc(F)c(=O)[nH]1

Procedure:
Example 15 was repeated, using 5-fluoro-6-hydroxy-5,6-dihydrouracil obtained in Example 5 for the 5-fluoro-6-isopropoxy-5,6-dihydrouracil. 5-fluorouracil was obtained as the product.
Reaction SMILES: [O:1]=[C:2]([C:12]([F:15])([F:14])[F:13])[C:3]([F:11])([F:10])[S:4]([O:7]CC)(=[O:6])=[O:5].FC(F)(F)C(O)=O>>[O:1]=[C:2]([C:12]([F:15])([F:13])[F:14])[C:3]([F:10])([F:11])[S:4]([OH:7])(=[O:6])=[O:5]
Reactant: CCOS(=O)(=O)C(F)(F)C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(F)(F)F)C(F)(F)S(=O)(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Ethyl 2-oxopentafluoropropanesulfonate (25.6 g, 0.10 mol) was stirred at 25° C. and treated with trifluoroacetic acid (17.1 g, 0.15 mol). The mixture was allowed to stand overnight, and then it was heated to reflux (60° C.) in a spinning band still. Fractional distillation of the mixture at a pot temperature below 100° C. gave 2-oxopentafluoropropanesulfonic acid (18.4 g, 0.081 mol, 81%) bp 73° C. (2.6 mm Hg).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[F:21][C:22]([F:37])([O:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH2:36])=[NH:35])[CH:30]=[CH:31][CH:32]=1)[CH:23]([F:25])[F:24]>>[F:21][C:22]([F:37])([O:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[N:36]=[C:5]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH:4]=[CH:3][N:35]=2)[CH:30]=[CH:31][CH:32]=1)[CH:23]([F:24])[F:25]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CN(C)C=CC(=O)c1c[nH]c2ccccc12
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c1

Procedure:
In accordance with the general procedure described in Example 32, reaction of 213 mg(1 mmol) of 3-dimethylamino-1-(3-indolyl)-2-propen- 1-one [described in EP-A-0 233 461] and 310 mg (1 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(3-indolyl)-2-pyrimidine-amine; m.p. 140°-142°, FAB-MS: 403 (M+ +1).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.P(OCCCC)(OCCCC)(OCCCC)=O>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C/C=C/C=O
Agent: CCCCOP(=O)(OCCCC)OCCCC
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 116 °C
Yield: 88.9 %

Procedure:
First, 8.07 g (113 mmol) of crotonaldehyde and 9.69 g (58.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.45 g (5.80 mmol) of tributyl phosphate was added. Then the mixture was heated under reflux for 4 hours while agitating at an internal temperature of 116° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.3 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 99%, yield of 88% based on benzenesulfonyl cyanide).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:4]2[C:5]([F:12])=[C:6]([F:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[C:3]=2[F:14])[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(c2c(F)c(F)c([N+](=O)[O-])c(F)c2F)CC1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Pentafluoronitrobenzene (10 g, 46.9 mmol) is cooled to 0° C. and treated dropwise with 1-methylpiperazine (5.2 ml, 47 mmol) in triethylamine (14 ml, 94 mmol). After 30 minutes at 0° C., the reaction mixture is allowed to reach room temperature. After one hour, the orange suspension is diluted with water (100 ml) and extracted with ether (3×100 ml). The combined organic layers are washed with saturated aqueous sodium chloride solution (100 ml), dried with magnesium sulfate and evaporated. Recrystallization from n-hexane-ether (1:1) yields 10 g of 1-methyl-4-(2,3,5,6-tetrafluoro-4-nitrophenyl)piperazine as red-brown crystals (73%): mp: 77°-78° C.; NMR(CDCl3):2.35(s,3H),2.54 (m,4H),3.44(m,4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:18])[C:5](=[N:10][NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:19]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1cccnc1)C(=O)OC
Product: COC(=O)c1nn(-c2cccnc2)cc(OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A mixture of methyl 4-methoxy-3-oxo-2-(pyridin-3-ylhydrazono)butanoate (52 g, 210 mmol) in N,N-dimethylformamide dimethyl acetal (80 mL, 600 mmol) was refluxed for 30 min. The mixture was allowed to cool to room temperature and stayed at room temperature overnight. The formed crystals were collected by filtration and washed with AcOEt to give the title compound (35 g, 64% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.98 (3H, s), 3.98 (3H, s), 7.48-7.54 (1H, m), 7.96 (1H, s), 8.04 (1H, ddd, J=8.4, 2.6, 1.5 Hz), 8.71 (1H, dd, J=4.9, 1.5 Hz), 8.93 (1H, d, J=2.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[C:11]2C(=O)O[C:14](C)([CH3:18])[O:13][C:12]2=[O:20])[OH:10])=[CH:4][CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:10])[CH2:11][C:12]([O:13][CH2:14][CH3:18])=[O:20])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=C(O)Cc2ccc(Cl)cc2)C(=O)O1
Solvent: CCO
Product: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Yield: 73 %

Procedure:
A solution of 5-(2-(4-chlorophenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (103 g, 347 mmol) in ethanol (718 mL) was refluxed for 3 hours. The reaction was cooled and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexane=0/100→20/80) to give 61 g of the title compound as an orange oil. (73% yield). LC/MS (FA) ES+ 241. 1H NMR (400 MHz, CDCl3) δ: 7.32-7.28 (m, 2H), 7.15-7.11 (m, 2H), 4.17 (q, 2H, J=7.2 Hz), 3.81 (s, 2H), 3.45 (s, 2H), 1.26 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]([C:29]1[S:30][C:31]([CH:34]=O)=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:16])/[CH:7]=[CH:34]/[C:31]1[S:30][C:29]([C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])=[CH:33][CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)s1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=O)OCc2ccccc2)s1
Reaction time: 0.5 h

Procedure:
Diethylphosphonoacetic acid tert-butyl ester (12 g, 48 mmol) was dissolved in tetrahydrofuran (50 ml), 60% sodium hydride (1.6 g, 41 mmol) was added at 0° C., and the mixture was stirred for 30 minutes. A solution of 5-formyl-2-thiophenecarboxylic acid benzyl ester (8.8 g, 36 mmol) in tetrahydrofuran (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][CH:42]([CH3:51])[C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>ClCCl>[C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)=[O:9])[CH2:47][CH2:46]1)(=[O:44])[CH:42]([CH3:51])[CH3:41]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)C(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.4 %

Procedure:
To a stirred mixture of 4-formylbenzoic acid (1.5 g, 10 mmol) in anhydrous dichloromethane (30 mL) was added triethylamine (2.52 g, 25 mmol), 1-hydroxybenzotriazole (1.5 g, 11 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (2.1 g, 11 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and 2-methyl-1-(piperazin-1-yl)propan-1-one (2.12 g, 11 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL×2), followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (2 g, yield 70%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.15 (d, 6H), 2.80 (brs, 1H), 3.39-3.80 (m, 8H), 7.58 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 10.07 (s, 1H); LC-MS (ESI) m/z: 289 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15](CO)[O:14][CH:12](O)[C@H:11]([CH2:18]O)[C@H:10]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].Cl>CO.O>[CH2:27]([N:34]1[CH2:18][C@H:11]([CH2:12][OH:14])[C@@H:10]([OH:20])[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OC[C@H]1OC(O)[C@H](CO)[C@@H](O)[C@@H]1OCc1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H](OCc2ccccc2)[C@@H]1O
Temperature: 46 °C
Reaction time: 3.5 h
Yield: 25 %

Procedure:
4-O-Benzyl-2-deoxy-2-C-hydroxymethyl-D-glucopyranose (6.0 g, 21.1 mmol) (preparation see WO 95/24391) was dissolved in methanol (200 ml). Sodium periodate (21.4 g, 100 mmol) in water (200 ml) was added dropwise over 15 min. The mixture was stirred at 45-47° C. for 3.5 h. The precipitate was filtered off and the mixture was concentrated and purified by flash chromatography on silica gel using ethyl acetate as eluent. The purified product of 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-xylo-pentodialdose was dissolved in methanol (50 ml) and benzyl amine (4.36 g, 40.7 mmol) and sodium cyanoborohydride (1.0 g, 15.9 mmol) was added. The mixture was stirred at room temperature for 3 days. Subsequently the mixture was acidified to pH=2 with conc. hydrochloric acid and evaporated to dryness. The residue was dissolved in water (50 ml), pH was adjusted to 10 with aqueous sodium hydroxide and the solution was extracted with methylene chloride. The organic phase was dried over magnesium sulphate, evaporated and purified on silica gel using ethyl acetate as eluent. This afforded (3R,4R,5R)-1-benzyl-3-benzyloxy-5-hydroxymethylpiperidin-4-ol as an oil (Yield: 25%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: Nc1cccc(Br)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cl)cc1Nc1cccc(Br)c1
Temperature: 150 °C
Yield: 61.1 %

Procedure:
(Method D-2) Under an atmosphere of nitrogen, 2,4-dichlorobenzoic acid (36 g, 0.19 mol), 3-bromoaniline (48 g, 0.28 mol), potassium carbonate (32 g, 0.23 mol), and copper powder (1 g, 0.016 mol, catalytic) were mixed in dry DMF (150 ml) and heated to 150° C. for 18 hrs. The DMF was removed under reduced pressure, water (200 mL) added and the mixture acidified with 2M HCl (400 mL) to give a brown solid which was collected by filtration. Recrystallisation from ethanol/water (60/40) gave the title compound (43 g, 0.116 mol 61%) as a grey solid. See, for example, Hodgeman et al., 1972.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:12](Cl)=[N:13][CH:14]=[N:15][C:16]=3Cl)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:12]([NH:32][S:29]([C:26]4[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:20])[CH3:21])=[CH:24][CH:25]=4)(=[O:30])=[O:31])=[N:13][CH:14]=[N:15][C:16]=3[O:1][CH2:5][CH2:4][OH:3])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1ncnc(Cl)c1Oc1ccc2c(c1)OCO2
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Oc2ccc3c(c2)OCO3)cc1

Procedure:
By reacting 5-(1,3-benzodioxol-5-yloxy)-4,6-dichloropyrimidine with p-tert-butylphenylsulfonamide and thereafter with ethylene glycol Na, there was obtained N-[5-(1,3-benzodioxol-5-yloxy)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-tert-butylbenzenesulfonamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)C#N)=[CH:5][CH:4]=1.C(C=C)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C#N)Nc2ccc(SC)cc2)cc1
Agent: C=CC=O
Product: COc1ccc(C=Nc2ccc(SC)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 21 (iii), but using α-(4-methoxyphenyl)-α-(4-methylthioanilino)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a white powder (yield 9%), melting at 183-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:30][SiH:31]([CH3:33])[CH3:32])([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]=O)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][O:37]CC1.O>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C@@:20]([O:30][SiH:31]([CH3:32])[CH3:33])([C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22][C:23]4[CH:24]=[CH:4][CH:3]=[CH:2][C:11]=4[C:39]([CH:38]=[O:37])=[O:34])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: C[SiH](C)O[C@](CCCC=O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Solvent: O
Product: C[SiH](C)O[C@](CCc1ccccc1C(=O)C=O)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C(C)(C)C
Temperature: 25 °C

Procedure:
To predissolved SeO2 (2.95 g, 26.57 mmol) in dioxane/H2O mixture (100 mL:0.48 mL) at 60∞C, was added the ketone from Step 1 (14.4 g, 26 mmol) in solution in dioxane (70 mL). The reaction mixture was heated at 100∞C overnight. The reaction was cooled to room temperature and filtered through a pad of celite and washed with dioxane (20 mL). Evaporation to dryness yielded the title compound which was used as such in the next step (Crude weight 14 g).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH2:31]([OH:34])[CH2:32][CH3:33].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu](I)I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:34][CH2:31][CH2:32][CH3:33])=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(I)cc3F)c2C#N)CC1
Reactant: CCCO
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCOc1ccc(Nc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C#N)c(F)c1
Temperature: 90 °C
Yield: 12 %

Procedure:
A mixture of 4-[5-cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (250 mg, 0.48 mmol), propan-1-ol (2 mL, excess), copper iodide (9.1 mg, 0.048 mmol), 1,10-phenanthroline (18.1 mg, 0.096 mmol) and cesium carbonate (313 mg, 0.96 mmol) in dioxane (3.5 mL) was heated under microwave irradiation for 30 min at 90° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide compound A65 as a white solid (10 mg, 12%). Exact mass calculated for C23H28FN5O4 457.50, found 458.8 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=O)[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[C:20]=2[OH:29])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)CC.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:29][C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: O
Product: COC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Yield: 91.3 %

Procedure:
A mixture of benzyl-3-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (210 mg, 0.5 mmol) in propionic acid (20 mL) was heated to reflux for 4 days. The mixture was diluted with water (50 mL), neutralized with sodium bicarbonate, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. 180 mg of methyl 2-(1-(benzyloxycarbonyl)piperidin-3-yl)benzo[d]oxazole-7-carboxylate was obtained. Yield: 91%. LC-MS (ESI) m/z: 395 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13]O>S(Cl)(Cl)=O>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(O)c(Br)c1
Reaction time: 2 h

Procedure:
3-Bromo-4-hydroxyphenylacetic acid (12.0 g, 0.052 mol) was dissolved in methanol and the solution was stirred at room temperature while thionyl chloride (ten drops) was added. The mixture was stirred for two hours and then concentrated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate and the solution extracted with diethyl ether (×3). The organic layers were collected, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give methyl-3-bromo-4-hydroxyphenylacetate as a golden oil (12.6 g).