Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=O.[C:13](=[S:16])([S-:15])[NH2:14].[NH4+]>CO>[OH:12][C:7]1[CH:6]=[C:5]([C:3]2[N:14]=[C:13]([SH:16])[S:15][CH:2]=2)[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: NC(=S)[S-]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc(-c2csc(S)n2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
10.0 g (53.6 mmol) of 2-chloro-3'4'-dihydroxyacetophenone was dissolved in 100 ml of methanol, and then 5.90 g (53.6 mmol) of ammonium dithiocarbamate was added thereto. The mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. To the residue, water was added to adjust the mixture to pH2.0, and then the mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and-then concentrated. The crystal residue was washed with diethyl ether to obtain 8.80 g (yield: 72.9%) of the above-identified compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:54][C:55]4[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=4)=[O:18])=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cccc(N)c1
Reactant: Nc1ncc2c(n1)CCN(c1ccc(C(=O)O)cc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2ccc(N3CCc4nc(N)ncc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.1 %

Procedure:
A mixture of 4-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 1.0 mL DMF was stirred at room temperature for 10 minutes. Then meta-toluidine (0.022 mL, 0.20 mmol) was added and the reaction heated at 55° C. for 18 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an EtOAc/hexane mixture to give the title compound as a light beige solid (18 mg, 51%). 1H NMR (DMSO-d6) δ: 9.84 (s, 1H), 8.12 (s, 1H), 7.85-7.92 (m, 2H), 7.60 (s, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.03-7.09 (m, 2H), 6.88 (d, J=7.6 Hz, 1H), 6.42 (s, 2H), 4.36 (s, 2H), 3.71 (t, J=6.0 Hz, 2H), 2.75 (t, J=5.9 Hz, 2H), 2.30 (s, 3H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(N(CC)CC)C.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](Cl)=[O:24]>C(O)C.[Pd]>[NH:6]1[CH:5]=[C:4]([NH:1][C:23](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[CH:8]=[N:7]1
Reactant: O=C(Cl)c1ccccn1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1cn[nH]c1)c1ccccn1
Reaction time: 3 h

Procedure:
A solution of 4-nitro-1H-pyrazole (2.5 g, 22 mmol) in ethanol (80 mL) was added to a Parr vessel under an argon atmosphere. Carefully into the vessel, 10% Pd/C (0.2 g) was added. The vessel was sealed and H2 was added to a pressure of 40 psi. The vessel was shaken for 3 hours and then the catalyst removed by filtration. The catalyst was washed with ethanol and the combined filtrates where evaporated to dryness under reduced pressure. The residue was dissolved in THF (350 mL), treated with triethyl amine (6.9 mL, 49 mmol) and cooled on an ice bath under an argon atmosphere. Picolinoyl chloride hydrochloride (3.94 g, 22.3 mmol) was added in one portion. When the reaction was complete, the solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution was extracted with water, NaHCO3 sat, dried, and the solvent removed under reduced pressure. The crude residue was re-crystallized from ethyl acetate to afford N-(1H-pyrazol-4-yl)picolinamide. (2.19 g, 52%). 1H NMR (DMSO-d6) δ 10.88 (s, 1 H), 8.7 (s, 1 H), 8.12 (m, 2 H), 8.04 (m, 1 H,), 7.96 (s, 1 H), 7.65 (m, 1 H). MS: m/z=189[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2ccccc2)cs1

Procedure:
The title compound was prepared from 2-amino-4-phenylthiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (51.8 mg) with purity >90%. MS (pos) m/z 365.1.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[OH:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][CH:10]=1>CCOCC>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:3]=[CH:2][C:1]([OH:7])=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(O)cc1
Solvent: CCOCC
Product: O=C(O)C=Cc1ccc(O)cc1

Procedure:
Sometimes it is convenient to derive the ether substituent from the hydroxyphenyl substituent at the same position the latter occupies, for example, in the following sequence of steps. Malonic acid and p-hydroxybenzaldehyde are reacted to form p-hydroxycinnamic acid, followed by esterification with methanol in the presence of conc H2SO4 to form the methyl ester. This ester is then reacted with TosMIC in the presence of NaH to form methyl 4-hydroxyphenylpyrrole-3-carboxylate ("P-carboxylate"). The P-carboxylate is then reduced with LiAlH4 in THF to the 3-methyl-4-hydroxyphenylpyrrole which is then reacted with allyloxybutyl bromide to yield the 4-(4-allyloxybutoxyphenyl-3-methyl-pyrrole.
Reaction SMILES: C([Li])CCC.[C:6]1([P:12](=[O:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:31]1(=[O:37])[O:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CCCCCC.O1CCCC1>[OH:37][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([CH:13]([P:12](=[O:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:36]
Reactant: O=C1CCCCO1
Reactant: CCCCCCCCCCCP(=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCC(C(=O)CCCCO)P(=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.6M n-Butyl lithium solution in hexane (56 ml) was added to a stirred solution of the phosphine oxide (31.0 g) in dry tetrahydrofuran (400 ml) at -40° to -45° C. under nitrogen. The deep orange solution was stirred for 10 minutes at -40° to -50° C., then a solution of valerolactone (9.0 g) in dry tetrahydrofuran was added. The pale solution was allowed to warm to room temperature, poured on to ice and extracted with ether. The extract was dried and evaporated and the residue was crystallised from ether-petroleum spirit to give 1-(5-hydroxypentanoyl)undecyl-diphenylphosphine oxide, m.p. 70° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH:17]=[O:18])=[N:2]1.[CH2:19]([Mg]Br)[CH:20]=[CH2:21]>O1CCCC1.C(OCC)C>[OH:18][CH:17]([CH2:21][CH:20]=[CH2:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1
Reactant: O=CCc1ccccc1-c1noc2ccccc12
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2 g of 2-[2-(1,2-benzisoxazol-3-yl)-phenyl]acetaldehyde in 50 ml of tetrahydrofuran at −78° C. under a nitrogen atmosphere was added 10 ml of a 1 M solution of allyl magnesium bromide in diethyl ether. The solution was warmed to room temperature and stirred for a further 2 h then quenched by addition of 50 ml of saturated aqueous ammonium chloride. The aqueous layer was extracted with 150 ml then 100 ml of dichloromethane and the combined organic extracts dried over sodium sulfate and evaporated to give crude product which was purified by chromatography eluting with 20% ethyl acetate in hexane, affording 1 g of 3-[2-(2-Hydroxy-4-pentenyl)phenyl]-1,2-benzisoxazole, 1H-NMR (200 MHz, CDCl3) d 5.8 (CH═CH2).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=[O:2].Br[C:11]1[CH:12]=[C:13]2[C:26]3[C:16]([CH2:17][C@@H:18]4[C@@H:23]([C:24]=3[CH:25]=1)[CH2:22][C@H:21]([NH:27][C:28](=[O:34])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:20][N:19]4[CH2:35]CC)=[CH:15][N:14]2[Si](C(C)(C)C)(C)C>>[CH2:30]([N:29]([CH2:32][CH3:33])[C:28]([NH:27][C@H:21]1[CH2:22][C@H:23]2[C@@H:18]([CH2:17][CH:16]3[C:26]4[C:13](=[CH:12][C:11]([OH:2])=[CH:25][C:24]2=4)[NH:14][CH2:15]3)[N:19]([CH3:35])[CH2:20]1)=[O:34])[CH3:31]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]21
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(O)cc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With nitrobenzene and 3-(13-bromo-1-tert-butyldimethylsilyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[O:19]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[O:19]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[CH:3]=2)=[CH:31][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
To a stifling solution of methyl 3-(6-chloropyrimidin-4-ylamino)benzoate (1.0 g, 3.8 mmol) and 4-phenoxy aniline (0.703 g, 3.8 mmol) in ethanol (5 mL) was added acetic acid (0.22 mL) and the reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled, ethanol was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). It was washed with NaHCO3 solution (5 mL) and brine (5 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to yield methyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoate (1 g, 66%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:39]4[CH2:40][CH2:41][N:36]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[O:29][CH:26]([CH3:28])[CH3:27])[CH2:37][CH2:38]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1ccccc1N1CCN(CC2CCCN(C(=O)C3(c4ccc(Cl)cc4)CCC3)C2)CC1
Yield: 36.9 %

Procedure:
Compound 11 was prepared using the method described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-isopropoxyphenyl)piperazine (0.63 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 11 (0.49 g, 37%); C30H40ClN3O2, LRMS (m/z)=511 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.[F:16][C:17]([F:51])([F:50])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]3[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=3)[CH:35]=2)[N:19]=1>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:46]([C:42]2[CH:41]=[C:40]([C:36]3[CH:35]=[C:34]([C:20]4[N:19]=[C:18]([C:17]([F:16])([F:50])[F:51])[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[N:21]=4)[CH:39]=[CH:38][N:37]=3)[CH:45]=[CH:44][CH:43]=2)(=[O:47])=[O:48])[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2cccc(-c3cc(-c4nc(-c5ccc(C(F)(F)F)cc5)cc(C(F)(F)F)n4)ccn3)c2)CC1
Temperature: 0 °C
Yield: 87.1 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methyl-piperazine (0.09 g, 0.9 mmol), triethylamine (0.09 ml, 0.63 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example 1.1) (0.20 g, 0.34 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane/hexane) yielded the title compound as a white solid (0.18 g, 88%). MS (ISP) 607.6 [(M+H)+]; mp 205° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:20])(=[N:17][C:18]#[N:19])=[O:16])=[CH:11][C:10]=1[F:21])(C)(C)C.Cl.C(OCC)(=O)C>ClCCl>[F:21][C:10]1[CH:11]=[C:12]([S:15]([CH3:20])(=[N:17][C:18]#[N:19])=[O:16])[CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1ccc(S(C)(=O)=NC#N)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=NC#N)c1ccc(CN)c(F)c1

Procedure:
A solution of (2-fluoro-4-(N-cyano-S-methylsulfonimidoyl)-benzyl)-carbamic acid tert-butyl ester (preparation 18c, 2.20 g, 6.38 mmol) in dichloromethane (20 mL) is cooled at 0° C. and treated with a solution of hydrogen chloride in ethyl acetate (4 M, 16 mL, 64 mmol). After 2 h all volatiles are removed under reduced pressure and the residue is purifed by preparative reversed phase HPLC (Gemini, gradient of acetonitrile in water, 0.04% NH3). ESI mass spectrum: [M+H]+=228; r.t. HPLC: 2.16 min (0-30AB).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.[Cu]I>[C:13]1([C:19]#[C:20][C:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc2occ(Br)c2c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=Cc1ccc2occ(C#Cc3ccccc3)c2c1
Temperature: 55 °C
Yield: 56 %

Procedure:
In a dry flask 3-Bromo-1-benzofuran-5-carbaldehyde (1 g, 4.4 mmol) were dissolved in anhydrous THF (50 ml). To this was added under Argon Bis (triphenylphosphine) palladium(II) chloride (160 mg, 0.2 mmol), TEA (2.81 mL, 5 eq.), CuI (40 mg, 0.2 mmol) and Phenylacetylene (897 mg, 8.8 mmol). The reaction was heated at 55° C. for 2 days. The crude was filtered through celite and purified on silicagel using as eluent cyclohexan-ethyl acetate (7-3) affording 680 mg (yield: 56%)
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Cl:20][C:21]1[S:25][C:24]([NH2:26])=[C:23]([C:27]2[NH:31][CH:30]=[N:29][N:28]=2)[CH:22]=1>>[Cl:20][C:21]1[S:25][C:24]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:13])[F:14])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])=[C:23]([C:27]2[NH:28][N:29]=[CH:30][N:31]=2)[CH:22]=1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: Nc1sc(Cl)cc1-c1nnc[nH]1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1sc(Cl)cc1-c1ncn[nH]1

Procedure:
The title compound was synthesized from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid and 5-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.178, method [7], MS (ESI) 454.1 (M+H).); 1H NMR (300 MHz, CD3C1) δ 11.93 (b s, 1H), 8.0 (s, 1H), 7.92-7.86 (m, 2H), 7.84-7.81 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.17 (s, 1H), 6.97 (d, J=9.34 Hz, 1H), 5.30 (s, 2H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([Cl:4])[CH:17]=[CH:16][C:15]=1[OH:20])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: Oc1ccc(Cl)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfuryl chloride (0.965 ml) was added to a stirred solution of 2-(benzyloxy)phenol (2.0 g) in dry toluene (20 ml) at 0° C. The mixture was warmed to RT and stirred overnight then cooled to 0° C. and quenched with ice-water before extracting with ethylacetate. The organics were dried, evaporated under reduced pressure and the residue purified by chromatography on silica eluting with DCM/isohexane (1:1). Yield 1.5 g
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[CH:29]=3)=[O:31])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Reactant: Cc1c(-c2ccn(C[C@@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccn(C[C@@H](C)NC(=O)c3cc(-c4ccco4)n[nH]3)n2)ccc(C#N)c1Cl
Yield: 73.9 %

Procedure:
The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.077 g, 0.280 mmol), 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.055 g, 0.308 mmol), DIPEA (0.073 ml, 0.420 mmol), HOBt (0.057 g, 0.420 mmol) and EDCI (0.081 g, 0.420 mmol) using the method of Example 34(d) affording 0.090 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.15-1.17 (m, 3H), 2.52 (s, 3H), 4.32-4.35 (m, 2H), 4.44-4.51 (m, 1H), 6.61 (d, 2H), 7.65-7.67 (m, 1H), 7.75-7.79 (m, 1H), 7.82 (d, 1H), 7.84 (d, 1H), 8.30 (m, 2H), 8.35 (m, 2H), 13.69 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[CH2:11]([O:13]C(=O)CBr)[CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[N:6]([CH2:12][CH2:11][OH:13])[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1nc2c([nH]1)CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1nc2c(n1CCO)CCCC2

Procedure:
This compound was prepared from 2-methyl-4,5,6,7-tetrahydrobenzimidazole by reaction with ethylbromoacetate followed by reduction with lithium aluminium hydride to give 2-(2-methyl-4,5,6,7-tetrahydrobenzimidazol-1-yl)ethanol. Reaction with ethyl 4-chloroacetoacetate following the procedure of 1 above gave the title compound as a red oil. NMR, CDCl3 : δ 1.26 (t, J=6 Hz, 3H); 1.80 (m, 4H); 2.40 (s, 3H); 2.49 (m, 2H); 2.57 (m, 2H); 3.44 (s, 2H); 3.67 (t, J=5 Hz, 2H); 3.92 (t, J=5 Hz, 2H); 4.13 (s, 2H); 4.20 (q, J=6 Hz, 2H).
Reaction SMILES: [ClH:1].Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN(C[CH2:56][N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)CC1>>[ClH:1].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc12
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)coc12

Procedure:
This compound is synthesized from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119, see example 80) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: FC(F)(F)c1cccc(OCCCBr)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(C(F)(F)F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.924 g of 1-(3-bromopropoxy)-3-trifluoromethylbenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.28 (1:1 EtOAc-heptane); Rt=5.43.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=O)[C:6]([C:12]([NH:14][C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:16]=2[CH2:24][CH3:25])=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:29])=O>>[CH2:1]([C:4]1[C:5]([Cl:29])=[C:6]([C:12]([NH:14][C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:16]=2[CH2:24][CH3:25])=[O:13])[C:7]([CH3:11])=[N:8][C:9]=1[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCc1c(C)[nH]c(C)c(C(=O)Nc2c(CC)cc(C)cc2CC)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: C=CCc1c(C)nc(C)c(C(=O)Nc2c(CC)cc(C)cc2CC)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.85 g (2.41 m mol) of 5-allyl-N-(2,6-diethyl-4-methylphenyl)-1,4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide and 5 ml of phosphorus oxychloride was heated under reflux for an hour. An excess of phosphorus oxychloxide was removed under vacuum, and the residue was dissolved in 100 ml of methylene chloride. Then the resulting solution was added into 150 ml of saturated sodium bicarbonate solution, followed by stirring for an hour at room temperature. The organic layer was washed with water, dried and concentrated by the conventional method. The resultant crystalline residue was recrystallized from ethyl acetate to give 0.84 g of the title compound, m.p. 192.5°-194° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[C:13]1([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2cc(-c3ccccc3)ccc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1

Procedure:
The title compound was prepared by reacting 2-methoxy-6-phenylnaphthalene (0.54 g, 2.30 mmol) with of pyridinium HCl (10 g) at 190° C. according to method B to yield 0.32 g (63%) of a light pink solid: mp 169–170° C.; 1H NMR (DMSO-d6): δ 7.12 (1H, dd, J=2.56 Hz, J=8.54 Hz), 7.16 (1H, d, J=2.56 Hz), 7.35–7.38 (1H, m), 7.47–7.50 (2H, m), 7.73 (1H, dd, J=1.71 Hz, J=8.54 Hz), 7.76–7.79 (3H, m), 7.85 (1H, d, J=8.54 Hz), 8.08 (1H, d, J=1.28 Hz), 9.82 (1H, s); MS (ESI) m/z 219 (M−H)−.