Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1O[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].[CH2:14]([NH2:17])[CH2:15][CH3:16]>>[CH2:1]([C:3]1[N:17]([CH2:14][CH2:15][CH3:16])[C:5](=[O:13])[C:6]2[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:8]=1)[CH3:2]
Reactant: CCCN
Reactant: CCc1nc2ccccc2c(=O)o1
Product: CCCn1c(CC)nc2ccccc2c1=O
Temperature: 110 °C
Yield: 29.1 %

Procedure:
A mixture of 2-ethyl-benzo[d][1,3]oxazin-4-one (541 mg, 3.1 mmol) and propylamine (254 μL, 3.1 mmol) were heated to 110° C. for 1 hour. The crude product was purified by column chromatography (10-40% ethyl acetate-hexanes) to yield the product as a white solid (195 mg, 29%). 1H NMR (CDCl3) δ 1.03 (t, 3H, J=7.4 Hz), 1.41 (t, 3H, J=7.3 Hz), 1.76 (sex, 2H, J=7.7 Hz), 2.86 (q, 2H, J=7.4 Hz), 4.05 (t, 2H, J=7.9 Hz), 7.42 (t, 1H, J=8.1 Hz), 7.63 (d, 1H, J=7.7 Hz), 7.70 (t, 1H, J=7.7 Hz), 8.24 (d, 1H, J=8.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[CH:4][CH:3]=1.[C:21](=O)(O)[O-].[Na+]>C(O)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[CH:21]=[N:20][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1NCc1ccc2ncccc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Clc1ccc2ncn(Cc3ccc4ncccc4c3)c2n1
Temperature: 300 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Intermediate 9 (0.200 g, 0.702 mmol) was dissolved in formic acid (1.0 ml) and heated to 300° C. and stirred for 12 h. The reaction mixture was poured into ice water and pH adjusted to 7-8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as yellowish brown solid (0.200 g, 97% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ8.88 (dd, J=4.0, 1.3 Hz, 1H), 8.70 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.73 (dd, J=8.7, 1.7 Hz, 1H), 7.52 (dd, J=8.3, 2.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 5.69 (s, 2H).
Reaction SMILES: CCO.[C:4]([NH:7][C@H:8]([CH2:24][O:25][CH3:26])[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=1)=[O:10])(=[O:6])[CH3:5].CCOC(C)=O>O=[Pt]=O.CS(C)=O>[C:4]([NH:7][C@H:8]([CH2:24][O:25][CH3:26])[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:17][CH:18]=1)=[O:10])(=[O:6])[CH3:5]
Reactant: COCC#Cc1ccc(CNC(=O)[C@@H](COC)NC(C)=O)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCO
Product: COCCCc1ccc(CNC(=O)[C@@H](COC)NC(C)=O)cc1

Procedure:
An EtOH solution (30 mL) of (R)-2-acetamido-3-methoxy-N-(4-(3-methoxyprop-1-ynyl)benzyl)propanamide ((R)-6) (1.00 g, 3.1 mmol) was treated with H2 (1 atm) in the presence of 10% PtO2 (50 mg) at room temperature (16 h). The mixture was carefully filtered through a bed of Celite®. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel with EtOAc as the eluant to obtain (R)-7 (510 mg, 51%) as a white solid: Rf=0.27 (EtOAc); mp 105-107° C.; [α]25D +3.0° (c 0.5, DMSO); IR (nujol) 3283, 3085, 1638, 1550, 1457, 1379, 1299, 1122, 979, 725, 605 cm−1; 1H NMR (CDCl3) 1.81-1.92 (m, CH2), 2.03 (s, CH3CO), 2.67 (t, J=7.8 Hz, CH2Ph), 3.33-3.46 (m, CHH′O, CH2O and 2 OCH3), 3.80 (dd, J=4.0, 9.1 Hz, CHH′O), 4.44 (d, J=5.7 Hz, CH2N), 4.50-4.57 (m, CH), 6.45 (br d, J=6.6 Hz, NHC(O)CH3), 6.70-6.75 (br t, CH2NH), 7.15-7.20 (m, 4 ArH); 13C NMR (CDCl3) 23.2 (CH3CO), 31.2, 31.9 (2 CH2), 43.3 (CH2N), 52.4 (CHCH2), 58.6, 59.1 (2 OCH3), 71.7, 71.9 (2 CH2OMe), 127.5, 128.8, 135.3, 141.4 (C6H4), 169.9, 170.2 (2C(O)); HRMS (M+Na+) (ESI+) 317.1784 [M+Na+] (calcd for C17H26N2O4Na+ 345.1790); Anal. Calcd. for C17H26N2O4: C, 63.33; H, 8.13; N, 8.69. Found: C, 63.12; H, 8.13; N, 8.64.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([NH:25][CH2:26][CH2:27][NH2:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18](=[O:19])[NH:25][CH2:26][CH2:27][NH:28][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) in THF (8 ml) was added at room temperature triethylamine (0.59 ml, 4.21 mmol), the mixture was cooled (ice-water) and a solution of commercially available N—BOC-ethylenediamine (1.82 ml, 11.5 mmol) in THF (8 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and subsequent crystallization from dichloromethane/hexane to yield the title compound (1.41 g, 96%) as a white solid. MS (ISN) 383.0 [(M−H)−], mp 106° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:16]3([N:19]4[CH:23]=[N:22][C:21]([Cl:24])=[N:20]4)[CH2:18][CH2:17]3)[CH2:15][O:14]2)=[CH:9][CH:8]=1>C(#N)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:16]2([N:19]3[CH:23]=[N:22][C:21]([Cl:24])=[N:20]3)[CH2:18][CH2:17]2)([OH:14])[CH2:15][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:9][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Solvent: CC#N
Product: OC(Cn1ccnc1)(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Yield: 32 %

Procedure:
A mixture of 13 g (191 mmol) of imidazole and 1 g (9 mmol) of potassium tert.-butylate in 100 ml of acetonitrile is refluxed under a nitrogen atmosphere. To this mixture there is added dropwise a solution of 18 g (61 mmol) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane in 30 ml of acetonitrile. The reaction mixture is refluxed for a further 10 hours and then concentrated by stripping off the solvent under reduced pressure. The residue which remains is taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulphate and then concentrated by stripping off the solvent under reduced pressure. The residue which remains is chromatographed on silica gel using a mixture of dichloromethane/ethanol=90:10 as the eluent. Concentration of the eluate gives 7.1 g (32% of theory) of 1-(4-chlorophenyl)-1-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-2-(imidazol-1-yl)-ethan-1-ol in the form of a solid of melting point 231° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 158A (6.31g, 21.7 mmol) and 30% aqueous acetic acid (100 mL) in TMF (50 mL) was stirred at 95° C. for 6 hours, cooled to room temperature, concentrated, treated with water, and extracted with dichloromethane. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 248 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][O:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[O:16]1[CH2:17][CH:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2COC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C2COC2)CC1
Yield: 100.9 %

Procedure:
To a solution of (1-oxetan-3-yl-piperidin-4-yl)-carbamic acid tert-butyl ester (134 mg, 0.52 mmol) in dichloromethane (2 mL) was added TFA (2 mL). After 15 minutes at ambient temperature the reaction mixture was concentrated in-vacuo and the residue loaded onto a 5 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo afforded the title compound as a colourless gum (82 mg, 100%). 1H NMR (400 MHz, CDCl3): 4.63-4.63 (m, 4H), 3.47-3.45 (m, 1H), 2.69-2.68 (m, 3H), 1.90-1.81 (m, 4H), 1.41-1.40 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22]Cl.Cl>C(Cl)Cl>[CH3:20][O:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: N#CCc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Ten grams of 4-hydroxybenzyl cyanide was dissolved in 80 ml of methylene chloride, followed by addition of 20 ml of diisopropylethylamine and 9.1 g of chloromethyl methyl ether at 0 C., and stirred overnight at room temperature. The reaction solution was poured into 2N hydrogen chloride, followed by extraction of methylene chloride and washing in saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate to obtain residue. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform to produce 12.8 g of 4-methoxymethyloxybenzyl cyanide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:14].[F:15][C:16]([F:27])([F:26])[S:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5]/[C:6](=[CH:22]\[C:21]1[CH:24]=[CH:25][C:18]([S:17][C:16]([F:27])([F:15])[F:26])=[CH:19][CH:20]=1)/[C:7]2=[O:14]
Reactant: COc1ccc2c(c1OC)CCC2=O
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1OC)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 4,5-dimethoxy-2,3-dihydro-1H-inden-1-one (165) (100 mg, 0.520 mmol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde (72) (118.4 mg, 0.572 mmol) and PTSA (178.9 mg, 1.414 mmol). The reaction was stirred at 120° C. for 6 h. The resulting reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 25% ethyl acetate in hexane to afford yellow coloured solid of (E)-4,5-dimethoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one intermediate 166.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([F:36])[CH:23]=1.CN([CH:40]=[O:41])C>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]([F:36])[C:25]([O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])=[C:26]([F:28])[C:27]=1[CH:40]=[O:41]
Reactant: CC(C)(C)C(=O)Oc1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Oc1c(F)cc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Add n-butyl lithium 1.6N (23 ml, 36.8 mmol) to diisopropylamine (5.0 ml, 35.6 mmol) in anhydrous THF (7 ml) at 0° C. Stir the resulting yellow solution for 30 min at 0° C. Add this LDA solution dropwise via canula to a solution of 2,2-Dimethyl-propionic acid 4-bromo-2,6-difluoro-phenyl ester (8.01 g, 27.33 mmol) in anhydrous THF (40 ml) at −78° C. over 40 min. Stir the resulting bright yellow solution for 1 h at −78° C. Add anhydrous DMF (2.8 ml, 35.0 mmol) and stir the mixture for 1.5 h at −78° C. Quench the mixture with dilute sulfuric acid and extract the product with EtOAc (×3). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields 8.35 g of the title compound (95% yield).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].C(N(CC)CC)C.[CH:13]([NH2:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:13]([NH:26][C:3](=[O:4])[CH2:2][Br:1])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Br)CBr
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CBr)NC(c1ccccc1)c1ccccc1
Yield: 19.4 %

Procedure:
A solution of 2.91 g (14.39 mmol) of bromoacetyl bromide in 40 ml was cooled to 0° C. and 2.1 ml (14.39 mmol) of triethylamine and 2.64 g (14.39 mmol) of benzhydrylamine were successively added. The reaction solution was then evaporated to dryness under reduced pressure, and the resulting residue was purified on silica gel with EA as mobile phase. The product crystallized from the product fractions was filtered off with suction, washed with a little cold diethyl ether and dried under reduced pressure, resulting in 0.85 g of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([CH3:18])[CH:11]=[CH:10]2)(=O)=O.[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1.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.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>[Cl:17][C:16]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH3:18])=[N:13]2)=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH:28]=[CH2:29]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Product: C=Cc1c(Cl)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 35.4 %

Procedure:
Pd(PPh3)4 (52 mg, 0.045 mmol) and PdCl2(PPh3)2 (32 mg, 0.045 mmol) were added to a mixture 7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl trifluoromethanesulfonate (1F) (194 mg, 0.45 mmol), tributyl(vinyl)stannane (0.17 mL, 0.58 mmol), lithium chloride (57 mg, 1.4 mmol) and 2,6-di-tert-butyl-4-methylphenol (cat. amount) in 1,4-dioxane (8 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with a NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 1G (50 mg, 35%). LCMS-ESI+ (m/z): 314.2, 316.2 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:17][C:18]([C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[C:28]([OH:29])[C:23]2=[N:22][C:21]=1[CH3:30])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.Br[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[F:40].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[Cl-].[Na+].O.C(Cl)(Cl)Cl.O>[F:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[CH2:32][O:29][C:28]1[C:23]2[N:24]([C:20]([C:18]([NH:17][C@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][OH:8])=[O:19])=[C:21]([CH3:30])[N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: Cc1nc2c(O)cccn2c1C(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(OCc3cc(F)ccc3F)cccn2c1C(=O)N[C@@H](CO)c1ccccc1
Temperature: 30 °C
Reaction time: 28 h
Yield: 72.1 %

Procedure:
A mixture of 8.5 mg of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxamide, 5.6 mg of α-bromo-2,5-difluorotoluene, 5.0 mg of potassium carbonate, and 700 μl of DMF was stirred at 30° C. for 28 hours. To the reaction mixture were added 1 ml of water, 0.5 ml of saturated brine, and 4 ml of chloroform to carry out a layer separation operation. The organic layer was concentrated under reduced pressure, and to the residue were added 300 μl of THF and 300 μl of 1 M hydrochloric acid, followed by stirring at room temperature for 6 hours. To the reaction mixture were added 300 μl of a 1 M aqueous sodium hydroxide solution and 100 of saturated aqueous sodium bicarbonate, followed by extraction with 3 ml of chloroform. The solvent was evaporated under reduced pressure and the obtained residue was purified by preparative HPLC to obtain 6.3 mg of 8-[(2,5-difluorobenzyl)oxy]-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH:15]=[CH2:16]>C1(NC2C=CC3C(=CC=CC=3)C=2)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:16][CH2:15][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(Nc2ccc3ccccc3c2)cc1
Product: CCCCOC(=O)CCOc1ccc(C(C)(C)C)cc1
Yield: 45.2 %

Procedure:
A solution of 25 g (0.167 mole) p-tert-butylphenol, 0.2 g sodium hydride (as 50% dispersion in oil), 0.2 g N-phenyl-2-naphthylamine (as basic polymerization inhibitor) in 75.0 g (0.586 mole ) butyl acrylate was heated at 125° C. for four hours. The temperature was then reduced in 100° C. and the excess acrylate distilled under gentle vacuum. The resulting oil was filtered through 900 g silica gel (90 to 200 mesh) using chloroform as eluant to yield 21.0 g pure butyl 3-(p-tert-butylphenoxy)-propionate (45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:18]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][C@@H:20]([CH3:24])[CH2:19]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C@@:18]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][C@@H:20]([CH3:24])[CH2:19]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12](/[C:15](=[N:28]/[OH:29])/[CH3:16])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CO[C@]1(c2cc(F)cc(Sc3ccc(C(C)=O)cc3)c2)CCO[C@@H](C)C1
Reactant: NO
Agent: Cl
Product: CO[C@]1(c2cc(F)cc(Sc3ccc(/C(C)=N/O)cc3)c2)CCO[C@@H](C)C1
Yield: 66 %

Procedure:
Using an analogous procedure to that described in Example 25, 4'-{5-fluoro-3-[(2S,4R)-4-methoxy-2-methyltetrahydropyran-4-yl]phenylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-fluoro-3-[(2S,4R)-4-methoxy-2-methyltetrahydropyran-4-yl]phenylthio}acetophenone oxime in 66% yield, m.p. 105° C.;
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>ClCCl.CN(C)C=O.N1C=CC=CC=1>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[CH3:7])=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Cc1oncc1C(=O)O
Reactant: Nc1cnc(Cl)c(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1oncc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.9 %

Procedure:
Oxalyl chloride (0.8 ml, 10.3 mmol) was added to a solution of 5-Methyl-isoxazole-4-carboxylic acid (1 g, 6.9 mmol) in dichloromethane (30 ml) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 5 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (3 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.65 g, 4.6 mmol) in anhydrous pyridine (30 ml) and the mixture heated at 50° C. for 3 hours before cooling to room temperature and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 1:1, to afford the product as a white solid (360 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12](O)[CH2:13][CH2:14][CH3:15].C(OC(C)C)(C)C>[Zn]>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CCCCO
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CCCCOC(=O)CCc1ccccc1

Procedure:
Under a nitrogen atmosphere, a mixture of 3-phenylpropionic acid (3.0 mmol), n-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 1 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, butyl 3-phenylpropionate was obtained quantitatively.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].CC(O)=O.[CH3:15][NH:16][CH3:17].[BH3-]C#N.[Na+]>CO>[CH3:15][N:16]([CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2])[CH3:17]
Reactant: CNC
Reactant: N#Cc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)Cc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
To a solution of 3-cyanobenzaldehyde (2.50 g, 19 mmol) in MeOH:AcOH (25 ml, 99:1) was added dimethyl amine (2.5 ml, 50 mmol) at 0° C., followed by NaBH3CN (1.80 g, 29 mmol). The mixture was stirred at 0° C. for 18 hours, then evaporated, taken up in EtOAc, washed with 5% KHCO3, brine filtered (Whatman® 1 PS phase separator) and evaporated. The residue was purified by flash chromatography on silica gel (eluant EtOAc:MeOH 98:2 v/v) to give the title compound (1.15 g, 38 %).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:6]1=2.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH:32][C:15]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:2]=4[F:1])[C:6]=3[CH:14]=2)=[O:17])[CH2:26][CH2:25]1
Reactant: CN1CCN(CCN)CC1
Reactant: O=C(O)c1cnc2c(c1)N(Cc1cc(F)ccc1F)CCN2
Product: CN1CCN(CCNC(=O)c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)CC1
Yield: 82 %

Procedure:
1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (40 mg) was reacted with 2(4-methylpiperazin-1-yl)ethylamine as in General Procedure 8 to give the title compound as an orange foam (82% yield). M.p. (foam), LCMS: m/z=431.09 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.28 (s, 3H), 2.41-2.58 (m, 6H), 3.12-3.23 (m, 4H), 3.53-3.39 (m, 2H), 3.42-3.51 (m, 2H), 3.58-3.67 (m, 2H), 4.49 (s, 2H), 5.33 s, 1H), 6.72 (s, 1H), 6.84-6.91 (m, 2H), 6.93-7.04 (m, 1H), 7.10 (s, 1H), 7.85 (d, J=1.5 Hz, 1H).