Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 1H-indazole-5-carboxylic acid (6.0 g, 1.0 eq), N,O-dimethylhydroxylamine hydrochloride (5.4 g, 1.5 eq), HOBt (6.0 g, 1.2 eq) and EDCI (8.5 g, 1.2 eq) in 100 mL CH2Cl2 was added Et3N (15 g, 4.0 eq) dropwise at 0° C. After addition, the mixture was stirred at rt overnight, concentrated, and purified by column chromatography to give the desired product (4.4 g, 58%). 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 3.56 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[CH3:12][NH2:13]>O>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:13][CH3:12])[N:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNCc1csc(C(C)C)n1
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of 40 g of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 100 ml of water was added dropwise with stirring to 400 ml of 40% aqueous methylamine. The resulting solution was stirred for 1 h, then concentrated in vacuo. The residue was taken up in chloroform, dried over Na2SO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography using 10% methanol in chloroform provided 21.35 g (55%) of the desired compound. 1H NMR (DMSO-d6) δ 1.34 (d, J=7 Hz, 6 H), 2.56 (s, 3 H), 3.30 (heptet, J=7 Hz, 1 H), 4.16 (s, 2 H), 7.63 (s, 1 H). Mass spectrum: (M+H)+ =171.
Reaction SMILES: [C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>>[C:4]([O:6][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])(=[O:5])[CH2:3][CH2:2][C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7]
Reactant: CN1C(C)(C)CC(OC(=O)CCC(=O)[O-])CC1(C)C
Reactant: CCCCCCCCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCC(=O)OC1CC(C)(C)N(C)C(C)(C)C1

Procedure:
The product is prepared as described in Example 4b by reacting 27.1 g (0.1 mol) of mono(1,2,2,6,6-pentamethyl-4-piperidyl) succinate with 33.3 g (0.1 mol) of 1-bromooctadecane in the presence of 10.1 g (0.1 mol) of triethylamine. The product obtained has a melting point of 38°-40° C. after crystallization from acetonitrile.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]([O:36][C:37]([N:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[C:48]([CH:49]=[O:50])[C:43]=2[O:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[C:32]([O:36][C:37]([N:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[C:48]([CH:49]([C:2]3[C:7]([N:8]([S:9]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=4)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=3)[OH:50])[C:43]=2[O:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(C=O)cccc21
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1cccc2c1OCCN2C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (2.92 g, 6.18 mmol) in THF (12 mL) under nitrogen atmosphere at −20° C. was added isopropylmagnesium chloride (2 M solution in THF, 6.5 mL, 13.0 mmol) via dropwise addition. The mixture was then stirred for 1 hour at 0° C. followed by the addition of a solution of 8-formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (273.5 mg, 1.54 mmol) in THF (2 mL) at −20 ° C. The mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×200 mL). The combined organic extracts were washed with saturated aqueous NH4Cl solution (40 mL) and brine (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (10% EtOAc-hexanes to 90% EtOAc-hexanes) to obtain 8-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl) -2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (590.2 mg) as yellow syrup. MS m/z: 678.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]([OH:16])[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH2:18]>>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]([OH:16])[CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[O:16]=[C:10]1[CH:9]2[CH2:15][CH2:14][CH:12]([CH2:13][N:18]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:11]1
Reactant: CC(C)(C)OC(N)=O
Agent: OC1CC2CCC1N(Cc1ccccc1)C2
Product: CC(C)(C)OC(=O)N1CC2CCC1C(=O)C2

Procedure:
2-benzyl-2-azabicyclo[2.2.2]octan-6-ol is prepared using a method analogous to that described in U.S. Pat. No. 5,147,873. 2-benzyl-2-azabicyclo[2.2.2]octan-6-ol is debenzylated and subsequently protected as the tert-butyl carbamate using procedures analogous to those described in Example 1. Oxidation of the resulting intermediate alcohol using the Swern protocol affords the title product.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2.[BrH:28]>>[Br:28][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2
Reactant: Br
Reactant: COc1cc2nc(N3CCc4c(CO)cccc4C3)[nH]c(=O)c2cc1OC
Product: COc1cc2nc(N3CCc4c(CBr)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
2-(5-Hydroxymethyl-3,4-dihyd ro-1H-isoquinolin-2-yl)-6,7-dimethoxy-1H-quinazolin-4-one 22a (0.2 g, 0.54 mmol) was dissolved to room temperature in 5 mL of 48% hydrobromic acid and stirred to room temperature for 24 h. The precipitated product was separated by filtration, rinsed with water, dried to yield 0.21 g (91%) 2-(5-bromomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 23a.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13]>N1CCCCC1.Cl.C(O)C>[C:12]([C:14](=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)[C:15]([NH2:17])=[O:16])#[N:13]
Reactant: N#CCC(N)=O
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=C(C#N)C(N)=O)ccc1O
Temperature: 25 °C

Procedure:
A reaction mixture of vanillin (1.52 g, 0.01 mol), α-cyanoacetamide (0.84 g, 0.01 mol), ethanol (25 mL) and piperidine (6 drops) is heated at reflux for 1 hour and then allowed to cool to room temperature. The reaction mixture is acidified to pH of about 3-4 by addition of a few drops of concentrated HCl. The product which is collected by filtration, washed with ethanol and dried in air has the following structure supported by mass spectrometry: ##STR23## The yield of product is 1.5 g (68.8%). In methylene chloride the product has an absorption maximum of 352 nm.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]([CH3:21])([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:7]([NH2:9])=[O:8])([CH3:5])[CH3:4].[CH3:22][OH:23]>>[C:7]([C:6]([NH:10][C:11]([C:12]1[N:13]=[CH:14][CH:15]=[CH:16][C:17]=1[C:18]([O:23][CH3:22])=[O:19])=[O:20])([CH3:21])[CH:3]([CH3:5])[CH3:4])(=[O:8])[NH2:9]
Reactant: CO
Reactant: CC(C)C(C)(C(N)=O)N1C(=O)c2cccnc2C1=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cccnc1C(=O)NC(C)(C(N)=O)C(C)C
Reaction time: 8 h

Procedure:
Sodium hydride (0.47 g of a 50% suspension in mineral oil) is reacted with 500 mL dry methanol under nitrogen. To this is added 51.4 g of 5,7-dihydro-alpha-isopropyl-alpha-methyl-5,7-dioxo-6H-pyrrolo [3,4-b]pyridine-6-acetamide and the mixture stired at room temperature overnight. The mixture is concentrated, the residue dissolved in methylene chloride and the solution washed first with 150 mL water followed by 150 mL brine. After drying (Na2SO4), the organic phase is concentrated and the residue crystallized from ether to give 47.85 g of product which is analytically pure mp 108°-145° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12](=[O:14])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Br[C:16]1C=C(C=CC=1C)C(=N)NO.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:16])[C:12](=[O:14])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=N)NO)cc1Br
Reactant: Cc1ccc(-c2noc(=O)[nH]2)cc1Br
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(=O)n2C)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step-2: 3-(3-Bromo-4-methylphenyl)-1,2,4-oxadiazol-5(4H)-one: To a 0° C. cooled solution of 3-bromo-N-hydroxy-4-methylbenzimidamide (500 mg, 2.18 mmol, 1.0 eq) in DCM (10 mL) was added triphosgene (250 mg, 0.87 mmol, 0.4 eq) followed by diisopropylethylamine (0.76 mL, 4.46 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction was cooled back down to room temperature and quenched with water (5 mL) followed by dilution with DCM. The layers were separated and the organic layer was washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum to afford 250 mg of the title product as white solid. 1HNMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H, D2O exchangeable), 8.01 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.0, 1.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H) 2.42 (s, 3H); ESI-MS (m/z) 255, 257 [(MH)+, Br79,81]
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:37][CH2:36][N:35]([C:41]4[CH:42]=[CH:43][C:44]([C:45]#[N:46])=[CH:47][CH:48]=4)[CH2:40][CH2:39]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][S:15][CH2:16][C@@H:8]12
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (80.0 mg, 0.318 mmol) was suspended in propionitrile (0.8 mL) and (cyanomethyl)trimethylphosphonium iodide (93.0 mg, 0.382 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (167 ul, 0.955 mmol). To the stirred mixture was then added 4-(piperazin-1-yl)benzonitrile (59.6 mg, 0.318 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with ethanol (5 mL) and dried in vacuum to afford the title compound (36.0 mg, 26.9%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 8.26 (br. s., 1H), 7.79 (d, J=1.8 Hz, 1H), 7.44-7.60 (m, 2H), 6.96 (br. s., 1H), 6.76-6.91 (m, 2H), 5.05 (dt, J=13.6, 2.7 Hz, 1H), 4.43 (dd, J=10.7, 3.2 Hz, 1H), 3.27-3.63 (m, 6H), 3.15 (td, J=12.8, 2.3 Hz, 1H), 3.00 (td, J=12.8, 2.7 Hz, 1H), 2.77-2.93 (m, 2H), 2.59 (br. s., 4H), 2.34-2.45 (m, 1H). [M+H] calc'd for C22H24N6OS, 421; found, 421.
Reaction SMILES: [C:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I([O-])(=O)(=O)=[O:16].[Na+]>C(OCC)(=O)C.O.O.[Ru](=O)=O>[C:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@H]1CCCCN1C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
Ruthenium(IV) oxide hydrate (0.8 g, 0.006 mol) then a solution of N-BOC-6(S)-methyl-piperidine (4.00 g, 0.020 mol) in ethyl acetate (240 ml) were added to a solution of sodium periodate (21.36 g, 0.100 mole) in water (200 ml) and strongly stirred for 24 hours at room temperature under argon atmosphere. After separation the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried with magnesium sulfate and then treated with activated carbon, giving a colorless solution that was evaporated on a rotavapor at 30° C. The residue (3.98 g) was purified by silicagel (125 g) column chromatography with cyclohexane-ethyl acetate (1-1, v/v), furnishing a product (2.50 g, 59% yield) which according to its 1H-NMR spectrum was pure enough for the next reaction step.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:4][C:5]([C:11]2([OH:38])[C@H:16]([O:17][Si](C)(C)C)[C@@H:15]([O:22][Si](C)(C)C)[C@H:14]([O:27][Si](C)(C)C)[C@@H:13]([CH2:32][O:33][Si](C)(C)C)[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[CH3:48]S(O)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:4][C:5]([C:11]2([O:38][CH3:48])[C@H:16]([OH:17])[C@@H:15]([OH:22])[C@H:14]([OH:27])[C@@H:13]([CH2:32][OH:33])[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(Cc2cc(C3(O)O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]3O[Si](C)(C)C)c3c(c2Br)CCC3)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Br)CCC3)cc1
Temperature: -40 °C

Procedure:
To a solution of crude alcohol 14 (2.03 g) in anhydrous THF (11.9 mL) were added CH3SO3H (0.6 N in MeOH, 7.0 mL, 4.18 mmol) at −78° C. under nitrogen atmosphere. The mixture was slowly warmed up to −40° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (15 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 15, which was used without further purification (0.94 g, 1.85 mmol, 80%). [M−OMe]+ 477.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCCC1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1CN
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1CNc1nc(Cl)nc2ccccc12
Yield: 33.8 %

Procedure:
2,4-Dichloroquinazoline (3.0g 0.015 mol) was stirred in a mixture of water (60 ml), tetrahydrofuran (100 ml), o-methylbenzylamine (1.83 g, 0.015 mol) and sodium acetate (1.38 g, 0.017 mol) for a total of 16 hours. The reaction mixture was evaporated under reduced pressure and crystallised from ethanol to give 2-chloro-4-(2-methylbenzylamino)quinazoline (1.44 g, 30%), m.p. 215°-217°.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[N:6]=[CH:7][NH:8][C:9]=1[CH2:10][S:11][CH2:12][CH2:13][N:14]=[C:15]=[S:16]>C(O)C>[NH2:2][NH:3][C:15]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:9]1[NH:8][CH:7]=[N:6][C:5]=1[CH3:4])=[S:16]
Reactant: NN
Reactant: Cc1nc[nH]c1CSCCN=C=S
Solvent: CCO
Solvent: O
Product: Cc1nc[nH]c1CSCCNC(=S)NN
Temperature: 25 °C

Procedure:
Hydrazine hydrate (0.01 mole) is added to a solution of 2-(4-methyl-5-imidazolylmethylthio)ethyl isothiocyanate (0.01 mole) in ethanol, and stirred for an hour at room temperature to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:21][C:3]1[C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)cccc1-c1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described for example 1, (3-bromo-2-methyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 2) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as dark brown amorphous solid. MS: 433.3 (MH+).
Reaction SMILES: C(O)C.[OH-].[K+].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[C:7]1=[O:16].[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>CS(C)=O>[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(=O)Oc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)Oc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
An ethanol solution of potassium hydroxide (16.6 g. in 400 ml.) was added to a stirred solution of indoline-2,3-dione (isatin) (43.6 g.) in dimethylsulphoxide (400 ml.). After 10 minutes a solution of 4-acetoxybenzyl bromide (76.3 g.) in dimethylsulphoxide (40 ml.) was added. The mixture was stirred for 72 hours and then poured into ice/water (~1000 ml.). The gum which first formed slowly crystallised. The solid which formed was recrystallised from methanol (500 ml.) to give 1-(4-acetoxybenzyl)indoline-2,3-dione as a solid, m.p. 159°-161° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:10]=1[O:11][C:12]1[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[C:15]2[N:20]=[C:19]([C:21]3[CH:35]=[C:34]([CH3:36])[C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:23]([CH3:37])[CH:22]=3)[O:18][C:16]=2[N:17]=1>ClCCl>[F:8][C:9]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:10]=1[O:11][C:12]1[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[C:23]([CH3:37])[C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:34]([CH3:36])[CH:35]=3)[O:18][C:16]=2[N:17]=1
Reactant: CCCc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
55 μl of trifluoroacetic acid were added to a solution of 39 mg of tert-butyl {-4-[5-(2,5-difluorophenoxy)-7-propyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate in 0.4 ml of dichloromethane, and the mixture was stirred at room temperature for 16 h. The reaction was then concentrated under reduced pressure, and the residue was triturated with diisopropyl ether, filtered off with suction and dried. This gave 21 mg (60%) of the title compound.
Reaction SMILES: C1N2CN3[CH2:10][N:4](C2)CN1C3.[CH:11]1[C:16]([C:17](CBr)=[O:18])=[CH:15][CH:14]=[C:13]([F:21])[CH:12]=1.[ClH:22]>C(Cl)(Cl)Cl.CCO>[ClH:22].[NH2:4][CH2:10][C:17]([C:16]1[CH:15]=[CH:14][C:13]([F:21])=[CH:12][CH:11]=1)=[O:18]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hexamethylenetetramine (1.42 g, 10.1 mmol) was added dropwise over 30 min to a solution of 2-bromo-4-fluoroacetophenone (2.0 g, 9.2 mmol) in dry CHCl3 (40 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. After completion of the reaction the solid precipitate formed was collected by filtration and washed with CHCl3. The solid obtained was suspended in EtOH (40 mL) and conc. HCl (4 mL) was added. The mixture was heated to 80° C. for 3 h, cooled to room temperature, and the solid formed was filtered off. The clear filtrate was concentrated to afford 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (1.5 g, crude) as yellow solid. MS (ESI) m/z: Calculated for C8H8FNO: 153.06. found: 153.9 (M+H)+
Reaction SMILES: [OH-].[K+].Cl.[NH2:4]O.[C:6]([C:10]1[N:14]([CH3:15])[N:13]=[C:12](C2C=C(C)NC=2C)[CH:11]=1)([O:8][CH3:9])=[O:7]>O.C(O)C>[C:6]([C:10]1[N:14]([CH3:15])[N:13]=[C:12]([NH2:4])[CH:11]=1)([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)c1cc(-c2cc(C)[nH]c2C)nn1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(N)nn1C
Yield: 81.2 %

Procedure:
A solution of potassium hydroxide (5.08 g, 90.7 mmol) in water (76 mL) and ethanol (76 mL) was added to a slurry of hydroxylamine hydrochloride (11.44 g, 169.5 mmol) in ethanol (127 mL). Then, 5-carbomethoxy-3-(2,5-dimethylpyrrolyl)-1-methylpyrazole (8.5 g, 36.6 mmol) was added and the mixture was refluxed under a nitrogen atmosphere for 65 h. The solvents were removed at reduced pressure and the residue was triturated with ether. Sodium sulfate was added and the heterogenous mixture was filtered. The filtrate was concentrated and the residue was chromatographed on Silica Woelm®TSC (300 g, ethyl acetate-hexane gradient) to give 4.61 g, 81% of 5-carbomethoxy-3-amino-1-methylpyrazole as a white solid mp 114° to 118° C.; 1H-NMR (CDCl3) σ 6.17 (s, 1H), 4.02 (s, 3H), 3.88 (s, 1H), 3.7 (br s, 2H); IR (KBr) 1719, 1551, 1263, 1102, 756 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH:9]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1
Reactant: Cc1cccc(Br)n1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a solution of 2-bromo-6-methylpyridine (302 mg, 1.76 mmol) an 10 mL THF at −78° C., was added a solution of lithium diisopropylamide (1.8 M in heptane/THF/ethylbenzene, 1.07 mL, 1.93 mmol). The bright orange/red mixture was treated with iodomethane (0.20 mL, 3.2 mmol). The mixture was stirred at −78° C. for 10 min, then was removed from the ice bath and stirred 30 min. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 20% EtOAc/hexanes gradient) to afford 157 mg of Intermediate 163.1 as a colorless oil. LCMS (2 min gradient) RT=1.26 min, 186.0 (M+H)+.