Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[O:15][CH3:16])(=O)=O.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:26]=[O:27])[C:20]=2[CH:19]=[CH:18]1>>[CH3:16][O:15][C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[CH2:6][N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:26]=[O:27])[C:20]=2[CH:19]=[CH:18]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: COc1ccc(COS(C)(=O)=O)c(OC)c1
Product: COc1ccc(Cn2ccc3c(C=O)cccc32)c(OC)c1
Yield: 24.7 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.03 g of 2,4-dimethoxybenzyl methanesulfonate and 2.00 g of indole-4-carbaldehyde as a starting material to give 602 mg of 1-(2,4-dimethoxybenzyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 15%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[CH3:26][O:27][NH2:28]>>[CH3:26][O:27]/[N:28]=[C:22](/[C:19]1[N:20]=[C:21]2[N:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[N:14]=[N:15][C:16]2=[N:17][CH:18]=1)\[CH3:23]
Reactant: CON
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Product: CO/N=C(\C)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 70.2 %

Procedure:
The title compound (22.2 mg, 64%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (30.0 mg, 0.09 mmol) and O-methyl-hydroxylamine hydrochloride (78.0 mg, 0.93 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, CDCl3) δ ppm 9.45 (s, 1H), 8.92 (d, 1H), 8.08 (d, 1H), 7.81 (d, 1H), 7.78 (s, 1H), 7.39 (dd, 1H), 6.16 (s, 2H), 4.13 (s, 3H), 2.33 (s, 3H). LCMS (method E): [MH]+=352, tR=5.43 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1.O.C(=O)(O)[O-].[Na+].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C(COC)OC>[O:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=3)[N:3]=2)[CH2:11][CH2:12]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1cc(Cl)nc(N2CCOCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
The carbonitrile 25B (2.3 g, 10.28 mmol) was dissolved in 80 ml of dimethoxyethane. To the solution were added 40 ml of water, sodium bicarbonate (3 equiv., 2.6 g), [4-(trifluoromethoxy)phenyl]boronic acid (1.2 equiv., 2.54 g) and the mixture was stirred at rt for 5′. The mixture was degassed and put under argon. A catalytic amount of tetrakispalladium was added and the mixture was heated at 100° C. overnight. The solvents were evaporated off and the residue was dissolved with ethyl acetate, washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give a beige solid. (2.0 g, 55.5% yield)1HNMR (DMSO, 400 MHz) δ 3.61 (4H, m), 3.72 (4H, m), 7.20 (1H, s), 7.79 (1H, s), 7.82 (2H, d, J=8 Hz), 8.35 (2H, d, J=8 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.Cl.[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=2)[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:16]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=2)[CH2:14][CH3:15])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCNCCCN1CCc2cc(OC)c(OC)c3c2C1CC3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCN1CCc2cc(OC)c(OC)c3c2C1CC3)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
2-Chlorobenzenesulfonyl chloride (246.1 mg, 1.17 mmol) was added to a solution of Ethyl-[3-(7,8-Dimethoxy-2,2a,4,5-tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-amine dihydro-chloride (400 mg, 1.06 mmol) and N,N′-diisopropylethylamine (1.01 ml, 6.4 mmol) in CH2Cl2 (20 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×20 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate and A 2.8 M solution of hydrogen chloride in ethanol (0.50 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (233 mg, 43%).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=O>[Pd].C(O)(=O)C.C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[CH2:10][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=O)c2ccncc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cccc(Cc2ccncc2)c1
Yield: 98.8 %

Procedure:
Ammonium formate (25 g) was added to a mixture of 4-(3-methoxybenzoyl)pyridine (27 g, 127 mmol) and 10% palladium on charcoal (7 g) in acetic acid (250 ml). The mixture was heated at reflux for 0.5 hr. The mixture was cooled and diluted with an equal volume of methylene chloride. The catalyst was removed and the solution concentrated in vacuo. The residue was dissolved in water and basified with sodium hydroxide. The mixture was extracted with ether. The extracts were dried and concentrated in vacuo to give the crude 4-(3-methoxybenzyl)pyridine (25 g, 99%) which was used without purification in the next step.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:1]1([N:7]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:30]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(-n2nc3c(c2NC2CCCCC2)CCCC3)cc1
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)N(c1c2c(nn1-c1ccccc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-amine (example 45) was reacted with cyclohexylisocyanate ([3173-53-3]) to give the title compound as colorless oil. MS: m/e=421.3 [M+H+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([OH:17])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+]>CC#N>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1cccc2ccc(N3CCOCC3)nc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2ccc(N3CCOCC3)nc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a stirred mixture of 2-morpholinoquinolin-8-ol (200 mg, 0.87 mmol) in MeCN (5 mL) was added ethyl bromoacetate (216 mg, 1.31 mmol) and K2CO3 (360 mg, 2.61 mmol). The mixture was stirred at 80° C. for 4 hours. After filtration, the filtrate was concentrated to give crude product which was used directly for the next step (250 mg, Yield 90%).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.Cl.[CH2:15]([O:18][NH2:19])[CH:16]=[CH2:17]>CN(C=O)C.CCOC(C)=O>[CH2:15]([O:18][N:19]=[CH:1][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[C:16]1[CH:5]=[CH:4][CH:3]=[CH:1][CH:17]=1
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Reactant: C=CCON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1ccc(C=NOCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
a solution of trans 4-formyl-cinnamic acid A (Y═CH═CH, R1, ═H, R3═H, 0.346 g, 1.96 mmol.) and B O-Allylhydroxylamine hydrochloride (0.258 g, 2.37 mmol.) dissolved in 2 mL of DMF was warmed at 50° C. and stirred for 5 h. Then the solution was diluted with AcOEt and washed with water. Organic layer was dried on Na2SO4 and then concentrated under reduced pressure to give 0.421 g of the intermediate C (2E)-3-(4-{[(benzyloxy)imino]methyl}phenyl)acrylic acid (93% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[C:12]([F:22])=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[CH:16][CH:15]=[CH:14]3)[CH3:10])[C:5]([NH2:23])=[N:4][CH:3]=1.[N:24]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:9]([C:11]3[C:12]([F:22])=[C:13]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]=[CH:16][CH:15]=[CH:14]4)[CH3:10])[N:24]=[N:23][C:5]2=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: CC(Nc1nc(Br)cnc1N)c1c(F)cc2ncccc2c1F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(c1c(F)cc2ncccc2c1F)n1nnc2ncc(Br)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 6-bromo-N2-(1-(5,7-difluoroquinolin-6-yl)ethyl)pyrazine-2,3-diamine (450 mg, 1.2 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite (82.0 mg, 1.2 mmol) in water (2 mL). After stirring at rt for 2 hours, the solvent was removed in vacuo. The residue was diluted with NaHCO3 (aq.), extracted with DCM. The organic layer was separated and washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow solid (423 mg, 91%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.01 (dd, 1H), 8.95 (s, 1H), 8.52 (d, 1H), 7.75 (d, 1H), 7.64 (dd, 1H), 6.77 (q, 1H), 2.30 (d, 3H). LCMS (method A): [MH]+=391/393, tR=5.59 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1cc(-c2ccccc2F)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-bromo-2-nitrobenzaldehyde (8.2 g, 36 mmol), 2-fluorobenzeneboronic acid (10.0 g, 71.6 mmol) and 2M K2CO3 (54 mL) in dioxane (250 mL) was degassed with nitrogen. Pd(PPh3)4 (3.9 g, 3.6 mmol) was added, and the resulting mixture was degassed again and heated to reflux for 90 minutes. The resulting mixture was then diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and brine. The EtOAc extract was dried with MgSO4, filtered, and concentrated in vacuo to yield a residue. The residue was purified by silica gel chromatography eluted with ethyl acetate and heptanes from 0:100 to 5:95 to yield a yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.[Cl:37][C:38]1[C:39]([C:48](F)(F)F)=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([CH3:48])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[CH2:36][CH2:35]2)=[O:46])[C:42]=1[CH3:43]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nn(CC(=O)N2CCN(c3ccncc3)CC2)c(C)c1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-pyridyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 8.28 (d, 2H), 7.18 (d,2H), 5.41 (s, 2H), 3.83 (m,2H), 3.72 (m, 4H), 3.63 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=388.1, found=388.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:37][C@H:34]([CH2:35][OH:36])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:22])[CH3:21])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: NC[C@H](O)CO
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (9.32 g, 20.8 mmol) synthesized in Example (106c) was dissolved in methanol (200 mL), and (S)-(−)-3-amino-1,2-propanediol (5.01 g, 55.0 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (10.13 g, 32.3 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, water (300 mL) and ethyl acetate (200 mL) were added to the resulting residue, and the solution was separated. The organic layer was washed with saturated brine, subsequently dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (9.32 g, yield 86%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:20]([O:31][CH3:32])[N:19]=[C:18]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[N:17]=1>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20]([O:31][CH3:32])[N:19]=[C:18]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1OC
Solvent: c1ccncc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OC
Reaction time: 36 h
Yield: 3.1 %

Procedure:
4-tert-Butyl-benzene sulphonyl chloride (286 mg) was added to a stirred solution of 4-amino-6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (EP 713875A1) (100 mg) in dry pyridine (2 ml) at room temperature and the resulting mixture stirred for 36 hours. The reaction was then partitioned between ethyl acetate (20 ml) and 2N aqueous hydrochloric acid (10 ml) and the organic phase separated, washed (2N aqueous hydrochloric acid 2×10 ml, water 2×10 ml), dried (MgSO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of pentane:ethyl acetate 25:75 changing to 0:100, then dichloromethane:methanol 95:5 gave 4-tert-butyl-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide as an off-white coloured solid (5 mg).
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]([CH2:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:16][CH:15]=3)[N:9]=2)C(C)=CC=1.Cl.NO.O.Cl>C(O)C>[CH:31]1([CH2:30][N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:10]3[N:9]=[C:8]([NH2:3])[CH:13]=[CH:12][CH:11]=3)=[CH:19][CH:18]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: Cc1ccc(C)n1-c1cccc(-c2ccc(CCN(CC3CCCCC3)CC3CCCCC3)cc2)n1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2ccc(CCN(CC3CCCCC3)CC3CCCCC3)cc2)n1
Temperature: 80 °C

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 134 mg (0.277 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-{4-[2-(bis-cyclohexylmethyl-amino)-ethyl]-phenyl}-pyridine, 96 mg (1.387 mmol) hydroxylamine hydrochloride, 1 mL water and 5 mL ethanol. The solution was heated at 80° C. for 35 h, cooled, and poured into dilute aqueous hydrochloric acid. The aqueous layer washed with ethyl acetate, the pH adjusted to 11 with 1 N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil was taken up in ether and precipitated using 1 N HCl in ether. The product was collected as a tan solid, mp 75-85° C., 68 mg (51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
4-bromo-1-chloro-2-(4-methoxybenzyl)benzene (226 g, 0.73 mol) was dissolved in methylene chloride (2240 mL) under a nitrogen protection and in a protection from light. To the resulting mixture was slowly added dropwise a solution of boron tribromide (357 g, 1.42 mol) in methylene chloride (1416 mL) at −78° C. After the completion of dropwise addition, the reaction mixture was warmed up to room temperature and reacted for 2 hr. TLC indicated the completion of reaction. To the reaction mixture was slowly added dropwise water in an ice-water bath. The methylene chloride phase was collected. The residual aqueous phase was extracted with methylene chloride (1 L) for two times. The organic phases were combined, washed with water for two times and with a saturated sodium chloride solution for one time, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 210 g of a product in a yield of 97%.
Reaction SMILES: C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH2:23][CH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH3:28])=[O:26]>ClCCl>[CH:14](=[N:23][CH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH3:28])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCC(N)C(=O)OC
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(N=Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Triethylamine (8.67 g) (supplied from Wako Pure Chemical Industries), 7.74 g of magnesium sulfate anhydrate and 4.55 g of benzaldehyde (supplied from Wako Pure Chemical Industries) were added to a suspension of 7.79 g of methyl 2-aminohexanoate hydrochloride (supplied from BACHEM) in 70 mL of dichloromethane, and stirred at room temperature overnight. The reaction suspension was filtrated and the filtrate was concentrated. Then 280 mL of ether was added to the residue. The resulting suspension was filtrated and the filtrate was concentrated. Again 280 mL of ether was added to the residue, and the filtration and the concentration were repeated in the same manner, to yield 10.0 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[N:7]([NH:11]C(=O)OCC)[CH:8]=[CH:9][CH:10]=1)=[O:5].[OH-].[K+]>C(O)C.O>[Cl:21][C:19]1[CH:20]=[CH:2][C:3]2[C:4](=[O:5])[C:6]3[N:7]([CH:8]=[CH:9][CH:10]=3)[NH:11][C:17]=2[CH:18]=1
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Yield: 99.4 %

Procedure:
A solution of [2-(2,4-dichlorobenzoyl)-1H--pyrrol-1-yl]carbamic acid, ethyl ester (102.4 g) in 500 ml of ethanol was treated with a solution of potassium hydroxide (84 g) in 200 ml of water and then the mixture was stirred under reflux for 1 hour. The ethanol was evaporated and the aqueous layer was washed with 3×500 ml of ether. The aqueous phase was then adjusted to pH 5 with 6N HCl and the product collected by filtration. Oven drying yielded 68 g of a yellow green powder, mp >300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][S:8][C:9](=[N:25][CH3:26])[C:10]2([N:17]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[N:19]=[CH:18]3)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[OH:16])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:31]([O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C:10]1([C:9]([S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1)=[N:25][CH3:26])[N:17]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[N:19]=[CH:18]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 11.7 %

Procedure:
A solution of 42.76 g (106 mmol) of the 2-((4-methoxybenzylthio)(methylimino)methyl) -2-(4-nitroimidazol-1-yl)cyclohexanol prepared in the Preparative Example 13 in 300 ml of tetrahydrofuran was dropped into a suspension of 5.13 g (60% dispersion in mineral oil, 128 mmol) of sodium hydride in 60 ml of tetrahydrofuran in a nitrogen atmosphere at room temperature in 20 minutes. The obtained mixture was further stirred at 50° C. for 10 minutes, followed by the addition of 13.2 ml (111 mmol) of benzyl bromide at 50° C. The obtained mixture was stirred at 50° C. for one hour and then under reflux by heating for 20 hours. The obtained brown suspension was cooled by allowing to stand, and poured onto ice-water. The obtained mixture was extracted with ethyl acetate. The obtained organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue (55.8 g) was purified by silica gel column chromatography [solvent: benzene/acetone (25:1 to 5:1)] to give 6.15 g of the title compound as a brown oil (yield: 12%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=2)=[N:6][CH:7]=1.C([O:36][C:37](=[O:40])[CH2:38]Br)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:38][C:37]([OH:40])=[O:36])=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCc1cc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C)cn2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C)cn2)ccc1OCC(=O)O

Procedure:
Alkylation of 4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-propylphenol with tert-butyl-bromo-acetate, followed by standard TFA hydrolysis (as described in previous examples) provided after chromatography the title compound as a white foam.