Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC2CCC(N)CC2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(OC2CCC(NC(=O)C3CC3)CC2)cc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of 4-(4-aminocyclohexyloxy)benzoic acid ethyl ester (4.15 g, 15.76 mmol) in DCM (40 mL) at 0° C. was added TEA (1.6 g, 15.7 mmol) followed by cyclopropane carbonyl chloride (1.98 g, 18.9 mmol) over a period of 1 hr. Stirring was continued at 0-5° C. for 2 h. Water (40 mL) was then added and extracted with EtOAc. The organic layer was washed with 2N HCl, satd.NaHCO3 and brine solution. It was dried and concentrated under vacuum affording 4.75 g (91%) of 4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzoic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution resulting from 206 mg. (1 m mole) of 3-hydroxy-5-trifluoromethylbenzoic acid* and 85 mg. (2 m moles) of a 56.6% oil suspension of sodium hydride in 2 ml. of dimethylsulfoxide is added 127 mg. (1 m mole) of benzyl chloride and the reaction mixture heated to 90° C. for 1-2 hours. The mixture is cooled to room temperature, diluted with 10 ml. of water and extracted with ether. The aqueous phase is separated and acidified with 6N hydrochloric acid. The precipitated produce is filtered, dried and sublimed at 125° C. and .05 mm pressure, m.p. 143°-145° C.
Reaction SMILES: C[C:2]1[C:8](C)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[NH2:10][OH:11].Cl[C:13](Cl)(Cl)[CH:14]([OH:16])O>>[CH:7]1[CH:8]=[CH:2][C:3]([NH:4][C:14](/[CH:13]=[N:10]/[OH:11])=[O:16])=[CH:5][CH:6]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Reactant: Cc1cccc(N)c1C
Product: O=C(/C=N/O)Nc1ccccc1

Procedure:
The starting material of 2,3-dimethyl aniline (1) was mixed and condensed with hydroxylamine and chloral hydrate to yield isonitrosoacetanilide (2), then to yield isatin (3) by acid-catalyzed cyclization and 2-amino-3,4-dimethyl-benzoic acid (4) by an oxidative ring cleavage reaction. The total yield of the first three steps was 37%. The steps involved in hydroxylamine and chloral hydrate, both of which were toxic. Additionally, the steps were a multi-phase reaction, requiring careful control on the reaction time and temperature. Under carefully-controlled conditions, 2-amino-3,4-dimethyl-benzoic acid (4) was diazotized to yield an iodide (5). The iodide was condensed with 2-hydroxyphenylacetic acid to yield 2-[2-(carboxymethyl)phenoxy]-3,4-dimethyl-benzoic acid (6), which was further cyclized to yield DMXAA. The total yield of the six steps was about 12%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[N:21][O:22][S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])[N:5]=[C:4]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:3]=1.[CH3:37][C:38](OC(C)=O)=[O:39]>>[C:38]([NH:1][C:2]1[N:6]([C:7](=[N:21][O:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])[N:5]=[C:4]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:3]=1)(=[O:39])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)ON=C(CCN2C(=O)c3ccccc3C2=O)n2nc(C(C)(C)C)cc2N)cc1
Product: CC(=O)Nc1cc(C(C)(C)C)nn1C(CCN1C(=O)c2ccccc2C1=O)=NOS(=O)(=O)c1ccc(C)cc1
Yield: 59 %

Procedure:
4.39 g (8.6 mmol) of 5-amino-3-tert.butyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)pyrazole are reacted with acetanhydride in the same way as in example 1, synthesis step 3. The crude product which is obtained is recrystallised from methanol. 2.8 g (59%) of 5-acetamido-3-tert.butyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)-pyrazole with a m. pt. of 195°-201° C. are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1C=N[CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].CC(C)([O-])C.[K+].C[O:26][C:27](=[O:30])[CH:28]=[CH2:29].Cl.[CH3:32][N:33](C=O)C>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:29][CH2:28][C:27]([OH:26])=[O:30])[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:32][N:33]=1)=[C:6]2[CH3:18]
Reactant: C=CC(=O)OC
Reactant: CN(C)C=O
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1c(-c2ccccn2)n(CCC(=O)O)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 0.700 g, 2.50 mmol) in DMF (7 mL) and cooled to 0° C. Potassium tert-butoxide (0.740 mg, 6.26 mmol) is added and the mixture is stirred at room temperature for 30 min, then lowered back into the ice bath. Acrylic acid methyl ester (0.680 mL, 7.52 mmol) is added, and the reaction mixture is stirred for 1.5 h. The reaction mixture is acidified to pH 1 using 1M aqueous HCl and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (dichloromethane-methanol, 9:1) to afford 3-(5-chloro-3-methyl-2-pyridinyl-indol-1-yl)-propionic acid as a white solid. MS (ESI) m/z 315.18 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].[PH2]([O-])=O.[Na+]>[Pd].O1CCOCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(=O)c1c(-c2ccccc2)[nH]c2ccc(C)cc12
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(-c2ccccc2)[nH]c2ccc(C)cc12
Yield: 45.8 %

Procedure:
A suspension of palladium on carbon (10%, 1 g) in dioxane (50 mL) was added to a solution of ethyl 5-methyl-α-oxo-2-phenyl-1H-indole-3-acetate (Description 4, 3.66 g) in dioxane (250 mL). A solution of sodium hypophosphite (10 g) in water (10 mL) was added and the mixture was heated under reflux for 10 h. Further palladium on carbon (10%, 1 g) and sodium hypophosphite (10 g) were added and the mixture was heated under reflux for 24 h. Further palladium on carbon (10%, 1 g) and sodium hypophosphite (10 g) were added and the mixture was heated under reflux for 24 h. The mixture was cooled, filtered through celite and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc (90:10) to give the title compound as a colourless solid (1.6 g, 47%). 1H NMR (360 MHz, CDCl3) δ0.86 (3H, t, J 7 Hz), 2.43 (3H, s), 3.73 (2H, s), 4.11-4.16 (2H, m), 6.96 (1H, dd, J 8, 1.8 Hz), 7.18 (1H, d, J 10.8 Hz), 7.28-7.46 (5H, m), 7.58 (1H, d, J 7.2 Hz), and 7.98 (1H, br s). m/z (ES+) 294 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]3[CH2:35][CH2:34][NH:33][CH2:32][C:25]=3[N:26]=[C:27]([CH2:29][O:30][CH3:31])[N:28]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[C:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]2[C:24]3[CH2:35][CH2:34][N:33]([C:2]4[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:32][C:25]=3[N:26]=[C:27]([CH2:29][O:30][CH3:31])[N:28]=2)=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COCc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Reactant: FC(F)(F)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1C(F)(F)F)C2
Product: Cl

Procedure:
The title compound was prepared using the general procedure set forth in Example 5 using 2-chloro-3-(trifluoromethyl)pyridine (0.084 g, 0.46 mmol), N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine (0.101 g, 0.31 mmol), potassium carbonate (0.128 g, 0.93 mmol) in DMF (2 mL). The title compound was obtained as a light yellow solid after formation and isolation of its hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[NH:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:16][CH:15]=1.CN(C)C=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][C:17]4[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)=[O:7])=[CH:11][CH:12]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccc(F)cc1
Yield: 19 %

Procedure:
To 3.96 parts of 1-(4-fluorobenzoyl)aziridine, dissolved in 16 parts of benzene, are added 3.25 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 90 parts of benzene and 45 parts of N,N-dimethylformamide. The whole is stirred and refluxed for 5 hours. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with methylbenzene. The combined organic phases are dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 1part (19%) of 4-fluoro-N-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]benzamide; mp. 193.7° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.ClCC[I:39]>C1COCC1.CCCCCC.O.[Au]>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([I:39])=[C:17]([O:19][CH2:20][O:21][CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCI
Reactant: COCOc1cc(NC(=O)OC(C)(C)C)cc2ccccc12
Agent: [Au]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1c(I)c(NC(=O)OC(C)(C)C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
A solution of 23 (0.435 g 1.43 mmol) in 5.7 mL anhydrous THF was cooled to −25° C. and treated with TMEDA (0.758 mL, 5.0 mmol) followed by n-BuLi (2.29 mL of a 2.5 M solution in hexane, 5.0 mmol) in a slow dropwise manner. The resulting gold solution was stirred for 2 h at −25° C. The reaction mixture was treated with 1-chloro-2-iodoethane (0.37 mL, 5.0 mmol) and stirred for 15 min at 25° C. The reaction was diluted with H2O (40 mL), extracted with Et2O (3×20 mL), and the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×15 cm, 0-7% EtOAc/hexane gradient) yielded 24 (490 mg, 80%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.03 (d, J=12.8 Hz, 1H), 7.78 (d, J=12.5 Hz, 1H), 7.42 (m, 2H), 7.14 (br s, 1H), 5.20 (s, 2H), 3.74 (s, 3H), 1.56 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 154.7, 152.6, 135.1, 134.8, 127.6, 127.4, 125.1, 125.0, 122.2, 113.0, 100.5, 87.7, 81.1, 58.5, 28.4; IR (film) νmax 3391, 2977, 2933, 1732, 1524, 1367, 1340, 1276, 1228, 1157 cm−1; FABHRMS (NBA/NaI) m/z 430.0507 (C17H20INO4+H+ requires 430.0515).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:25]([Si:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:25]([Si:29]([CH3:30])([CH3:31])[O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:21][C:16]1[C:15]([N+:22]([O-:24])=[O:23])=[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[N:19]=[C:18]([CH3:20])[N:17]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(OCCCCO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])c(N2CCC(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 7) was treated with tert.-butyl-(4-chlorobutoxy)dimethylsilane and potassium carbonate in N,N-dimethyl-formamide at 80° C. to yield the 4-[4-(tert-butyl-dimethyl-silanyloxy)-butoxy]-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-pyrimidine as a yellowish oil; MS: [M+H]+=519; and the 3-[4-(tert-butyl-dimethyl-silanyloxy)-butyl]-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4 one as a yellowish oil; MS: [M+H]+=519.
Reaction SMILES: [CH3:1][CH2:2]N(C(C)C)C(C)C.[SH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[C:18]1[N:23]=[C:22]([S:24][CH3:25])[N:21]=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:19]=1[C:35]#[N:36].Cl>CCO.C(Cl)Cl>[CH2:1]([N:23]1[C:18]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:19]([C:35]#[N:36])[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)=[N:21][CH:22]1[S:24][CH3:25])[CH3:2]
Reactant: CSc1nc(Cl)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CS
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CSC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)=NC(SC)N1CC
Reaction time: 1 h

Procedure:
DIPEA (15.7 ml) was added to a stirred solution of ethyl 2-mercaptoacetate (9.3 ml) and 6-chloro-5-cyano-4-(3-nitrophenyl)-2-methylthio-pyrimidine (example 9(b), 26.0 g) in a mixture of EtOH (250 ml) and DCM (250 ml). After 1 h at room temperature, 0.1N aq. HCl (500 ml) was added to the mixture which was then extracted with DCM (3*500 ml), dried (MgSO4) and concentrated under reduced pressure.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([CH:26]2[CH2:28][CH2:27]2)[N:22]=1.O>CN(C)C=O>[CH:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:20][C:21]2[O:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[N:22]=2)=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: ClCc1nc(C2CC2)no1
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Oc1ccc(OCc2nc(C3CC3)no2)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
5 g of 4-(sec-butyloxy)-phenol and 6.2 g of potassium carbonate are stirred in 50 ml of anhydrous dimethylformamide for 1 hour at 80° C. Subsequently, 4.8 g of 5-chloromethyl-3-cyclopropyl-1,2,4-oxadiazole in 20 ml anhydrous dimethylformamide is dripped in and the mixture stirred for 8 hours at 80° C. and overnight at room temperature (about 20° C.). The mixture is then poured into 100 ml of water and extracted three times with ethyl acetate, and the organic phases are dried over magnesium sulfate. The solvent is evaporated off and the crude product is purified by chromatography on silica gel using n-hexane/ethyl acetate (4:1) as eluant. There is obtained 6.7 g of 5-[4-(sec-butyloxy)-phenoxymethyl]-3-cyclopropyl-1,2,4-oxadiazole as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][NH2:28])[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].CCN(C(C)C)C(C)C.[Br:42][CH2:43][CH2:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][NH:28][C:46](=[O:47])[CH2:45][CH2:44][CH2:43][Br:42])[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c2)ncn1
Reactant: O=C(Cl)CCCBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCBr)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c2)ncn1
Reaction time: 0.5 h

Procedure:
5-(6-Aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (52.5 mg, 0.117 mmol) is dissolved in DCM (5 mL) at 0° C. DIEA (0.025 mL, 0.143 mmol) is added followed by 4-bromo-butyryl chloride (0.020 mL, 0.172 mmol). The reaction is stirred for 30 min before being diluted with ethyl acetate and washed with water. The organic layer is removed, dried, and concentrated to provide the title compound. MS (ESI) m/z 595.6 (M+1).
Reaction SMILES: Cl.C[NH:3]OC.C(N(CC)CC)C.Cl[C:14]1[C:15](Cl)=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19](Cl)=[O:20].O>ClCCl>[C:19]([NH2:3])(=[O:20])[C:18]1[CH:22]=[CH:14][CH:15]=[N:16][CH:17]=1
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 167.7 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (2.25 g, 0.023 mol) was slurried in dichloromethane (40 mL) and cooled in ice-acetone. Triethylamine (4.7 g, 0.047 mol) was then added dropwise, followed by a solution of 5,6-dichloronicotinoyl chloride (4.5 g, 0.021 mol) in dichloromethane (25 mL). The resultant mixture was allowed to warm to room temperature and stirred for one hour. Water (50 mL) was added and the mixture separated. The organic phase was washed with water, 1M hydrochloric acid, 10% sodium carbonate solution and brine. It was then dried (Na2SO4) and evaporated to dryness to give the desired product (4.3 g, 86%) as a yellow oil which crystallized on standing.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.O>CN(C)C=O.C(OCC)(=O)C>[C:29]1([C:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:9])[CH2:24][CH:25]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Nc1ccccc1)c1ccccc1
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)N(CCCN1CC=C(c2ccccc2)CC1)c1ccccc1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
A solution of N-phenylbenzenesulphonamide (2.34 g) in dry N,N-dimethylformamide (10 cc) is added dropwise to a suspension of sodium hydride (0.24 g, 80% suspension in oil) in N,N-dimethylformamide (50 cc). After 15 minutes' stirring, a solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine (2.34 g) in N,N-dimethylformamide (20 cc) is added. The reaction mixture is heated to 140° C. for 1 hour and then cooled and poured into a mixture of water (200 cc) and ethyl acetate (200 cc). The organic phase is washed with water, is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 40-cm height) and eluted with dichloromethane and with a mixture of dichloromethane and ethanol (98-2 and 96-4 by volume), fractions 250-cc being collected. Fractions 5 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization from isopropyl ether (150 cc), N-[3-(4-phenyl-1,2,3,6-tetrahydropyridyl)propyl]-N-phenylbenzenesulphonamide (2.4 g) is obtained, melting at 112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]#N)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19].CC[O:33]C(C)=O>CCOCC.C(Cl)Cl>[CH2:16]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC1CCN(CCCC#N)CC1
Reactant: CCOC(C)=O
Reactant: Ic1ccccc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC1CCN(CCCC(=O)c2ccccc2OCc2ccccc2)CC1
Temperature: 40 °C
Yield: 51 %

Procedure:
In a 25 mL oven-dried flask was added Mg turnings (123 mg, 5.1 mmol) which was activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a solution of 1-benzyloxy-2-iodo-benzene (25) (1.18 g, 3.8 mmol) in Et2O (10 mL) and the reaction mixture was allowed to reflux for 3.5 hours. A solution of 4-(4-n-butylpiperidin-1-yl)butanenitrile 4 (0.53 g, 2.5 mmol) dissolved in CH2Cl2 (3 mL) was added and the reaction mixture and was stirred at 40° C over-night. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and left stirring for 1 hour, followed by addition of NaOH (20 mL, 2 M) until basic conditions. The reaction mixture was extrated with ethyl acetate (3×50 mL)) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce 1.28 g of crude 26. The crude product was subjected to CC [eluent: Tol: EtOAc (1:1)] to give pure 26 (0.51 g, 51%); LC-MS [M +H]+ 393 (cald. 393.7).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Cl-:15].[CH3:1][N+:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCNC(=O)c1ccccc1
Reactant: ClCc1ccccc1
Solvent: CC#N
Product: C[N+](C)(CCNC(=O)c1ccccc1)Cc1ccccc1
Product: [Cl-]

Procedure:
A solution of 19.23 grams (0.10 mol) of the N-(2-dimethylaminoethyl)benzamide, prepared as described in Example 1, 12.66 grams (0.10 mol) of α-chlorotoluene and 64 milliters of acetonitrile was heated at reflux for 19.75 hours. Solid crystallized on cooling which was collected, washed with acetonitrile and dried. The yield of product was 24.0 grams (75.27% of theory); mp=175°-176° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12](=[O:15])[C:11]3[N:7]([CH:8]=[CH:9][CH:10]=3)[C:6]=2[CH:16]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][C:12](=[O:15])[C:11]4[N:7]([CH:8]=[CH:9][CH:10]=4)[C:6]=3[CH:16]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)-n1cccc1C(=O)CO2
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)-n2cccc2C(=O)CO3)ncc1Cl

Procedure:
2-[5-Chloro-2-(4-oxo-4,5-dihydro-6-oxa-10b-aza-benz[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 9-Amino-6-oxa-10b-aza-benz[e]azulen-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1223c. Product was obtained as a tan ppt. MP 223-225 (dec) LCMS 493.09 (M+H), HPLC purity 95%, 1H-NMR (DMSO-D6, 400 MHZ) Δ 9.56 (s, 1H), 9.48 (s, 1H), 8.52 (d, J=4.6 Hz, 1H), 8.23 (s, 1H), 7.68 (s, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.17-7.10 (m, 2H), 7.08 (s, 1H), 6.53 (d, J=2.5H, 1H), 4.67 (s, 2H), 2.73 (d, J=4.5 Hz, 3H).