Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]([CH3:31])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]([CH3:31])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(Cc1ccnc(NC(=O)OC(C)(C)C)c1)Oc1ccc([N+](=O)[O-])c2ccccc12
Agent: [Pt]
Solvent: CO
Product: CC(Cc1ccnc(NC(=O)OC(C)(C)C)c1)Oc1ccc(N)c2ccccc12
Yield: 99.8 %

Procedure:
A solution of tert-butyl 4-(2-(4-nitronaphthalen-1-yloxy)propyl)pyridin-2-ylcarbamate (48) (271 mg, 0.614 mmol) in MeOH (30 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo to afford the title compound (49) (241 mg, 100%) as a purple foam: m/z 394.0 (M+H)+ (ES+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][CH:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[NH:3]1.[CH3:18][NH2:19].Cl>>[CH3:18][NH:19][C:8]([C:7]1[C:2](=[O:1])[NH:3][C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])=[CH:5][CH:6]=1)=[O:9]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)F)[nH]c1=O
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(C(F)(F)C(F)F)[nH]c1=O

Procedure:
At room temperature, 300 mg (1.19 mmol) of methyl 2-oxo-6-(1,1,2,2-tetrafluoroethyl)-1,2-dihydropyridine-3-carboxylate were stirred in 3.3 ml of a 40% strength aqueous methylamine solution for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, and the mixture was extracted with dichloromethane. Drying and concentration of the extract gave 230 mg (77% of theory) of the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]#[N:17])=[CH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCCl>[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][N:1]1[CH2:2][CH2:3][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]#[N:17])=[CH:8][CH2:7]2)[CH2:5][CH2:6]1
Reactant: N#CC1=CCC2(CCNCC2)c2ccccc21
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)CCN1CCC2(CC=C(C#N)c3ccccc32)CC1
Reaction time: 8 h

Procedure:
A solution of 2H-spiro[naphthalene-1,4′-piperidine]-4-carbonitrile (A4) (66 mg, 0.3 mmol), 3,3-dimethylbutanal (46 mg, 0.46 mmol) in 1,2-dichloroethane (5 ml) was stirred at 40° C. for 2 h. To the solution was added sodium triactoxyborohydride and the resulting mixture was stirred overnight, followed by treatment of MeOH (1 ml). Evaporation and the residue was dissolved in MeOH (2 ml) and purified by reverse phase C-18 HPLC to give 1′-(3,3-dimethylbutyl)-2H-spiro[naphthalene-1,4′-piperidine]-4-carbonitrile (Compound No. 51). LC-MS: m/e=309.1 (M+H). Rt=1.92 min. 1H-NMR (500 MHz, DMSO-d6): 9.03 (br. s, 1H), 7.49-7.40 (m, 4H), 7.12 (t, 1H), 3.45 (d, 2H), 3.22-3.11 (m, 4H), 2.78 (d, 2H), 2.03 (td, 2H), 1.88 (d, 2H), 1.58-1.54 (m, 2H), 0.92 (s, 9H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1CCCCC1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc2c(-c3cccc(C#Cc4ccccc4)c3)c(Cc3ccccc3)cnc12
Temperature: 90 °C
Yield: 77.7 %

Procedure:
A solution of 3-benzyl-4-(3-ethynyl-phenyl)-8-trifluoromethyl-quinoline (80 mg, 0.2 mmol), iodobenzene 84 mg, 0.4 mmol), piperidine (80 mg, 0.9 mmol) in toluene (2.0 mL) is treated with Pd(Cl)2(PPh3)2 (8.0 mg) and heated at 90° C. for 3 h. The reaction is then cooled and concentrated in vacuo. The residue is taken up in ethyl acetate and washed with 10 mL (1N HCl). The organic layer is dried and concentrated in vacuo to provide after chromatography 72 mg (75%) of the title compound. MS (ES) m/z 464.1.
Reaction SMILES: C(OC(=O)NCCCN)(C)(C)C.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[N:23]=[C:24]([N:27]([CH2:35][CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C)[C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[O:29])[S:25][CH:26]=1.C(O)(C(F)(F)F)=O.ClCCl>>[NH2:38][CH2:37][CH2:36][CH2:35][N:27]([C:24]1[S:25][CH:26]=[C:22]([C:14]2[O:13][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH:15]=2)[N:23]=1)[C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Agent: CC(C)(C)OC(=O)NCCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
According to the procedure in Example 19, (3-amino-propyl)carbamic acid tert-butyl ester was transformed into tert-butyl 3-(N-(4-(benzofuran-2-yl)thiazol-2-yl)thiophene-2-carboxamido)propylcarbamate, which was reacted with TFA/dichoromethane (3:2), stirred at room temperature for 30 min, concentrated in vacuo, then dissolved in MeOH and treated with 1M HCl/ether. The resulting precipitate was filtered and dried in vacuo to provide N-(3-aminopropyl)-N-(4-(benzofuran-2-yl)thiazol-2-yl)thiophene-2-carboxamide (220 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[C:13]1([CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:23][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21][CH3:22])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: CCCC(N)c1ccccc1
Product: CCCC(NC(=O)c1ccc(OC)c(C)c1)c1ccccc1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1-phenyl-butylamine. MS (M+H, 298.2).
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([F:14])[C:3]=1[CH3:15].[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:14])[C:3]=1[CH3:15]
Reactant: CCOC(=O)c1cc(F)c(N)c(C)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(N)c(F)cc(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 50 ml of ethanol was dissolved 8.91 g of ethyl 4-amino-2,5-difluoro-3-methylbenzoate, and 50 ml of 2N aqueous sodium hydroxide solution was added to the solution, after which the resulting mixture was stirred at room temperature for three hours. To the reaction mixture was added 50 ml of 2N hydrochloric acid, and the resulting crystals were collected by filtration, to obtain 5.45 g of colorless, crystalline 4-amino-2,5-difluoro-3-methylbenzoic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)[CH:7]=[CH:6]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)[CH:7]=[CH:6]3)=[CH:26][CH:25]=1
Reactant: NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(CNCc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 55.3 %

Procedure:
A solution of (6-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (example 54, step A) (130 mg, 0.45 mmol), 4-fluorobenzaldehyde (61 mg, 0.49 mmol) and acetic acid (108 mg, 1.8 mmol) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-borohydride (222 mg, 0.94 mmol) was added, the reaction mixture was allowed to stir for 2.5 days at room temperature, poured into ice/saturated sodium bicarbonate solution (30 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as a colorless oil (99 mg, 55%). MS: m/e=398.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[C:5]2=[CH:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].CN(C)C=O>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[C:5]3=[CH:16][NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:22][CH:23]=2)=[CH:34][CH:33]=1
Reactant: COc1cc2c(cc1Br)C(=CNc1ccc(CN3CCCCC3)cc1)C(=O)NC2=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1-c1ccc(F)cc1)C(=CNc1ccc(CN3CCCCC3)cc1)C(=O)NC2=O
Temperature: 110 °C
Yield: 49.2 %

Procedure:
A mixture of 6-Bromo-7-methoxy-4-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (272 mg, 0.578 mmole), N,N-dimethylformamide (2 mL), 4-fluorophenylboronic acid (202 mg, 1.44 mmole), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (78 mg, 0.075 mmole), tri(t-butyl)phosphine (28 mg, 0.138 mmole) and cesium carbonate (377 mg, 1.16 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chlororform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo and treated with acetonitrile, filtered and dried to give a yellow-brown solid 138 mg (48%), mp 227-230° C.; MS (ESI): m/z 486.2 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: NC(=O)c1nc[nH]n1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)c1nc(C(N)=O)n[nH]1
Reaction time: 24 h

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 7.4 g. of palmitoyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred. at room temperature for 24 hours. The mixture is filtered and the solid is washed successively with diethyl ether, cold water, diethyl ether and then dried in vacuo for 4 hours. The solid is extracted with hot dry acetonitrile and cooled yielding a colorless solid. The solid is redissolved by heating the mixture and allowed to recrystallize from the clear, colorless solution. The product is collected, washed with acetonitrile and dried in vacuo for 3 hours, yielding 0.75 g., m.p. 145°-160° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][O:18][C:17]4[CH:20]=[C:21]5[C:25](=[CH:26][C:16]3=4)[CH2:24][CH2:23][O:22]5)[C:8]2=[O:27])=[CH:4][CH:3]=1.OC1C=C(C=CC=1)C[N:35]1C2C(=CC=CC=2)[C:37]2(COC3C=C4C(=CC2=3)CCO4)[C:36]1=[O:55]>>[O:27]=[C:8]1[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:37][C:36]([NH2:35])=[O:55])=[CH:29][CH:28]=1
Reactant: O=C1N(Cc2ccc(O)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1N(Cc2cccc(O)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Product: NC(=O)COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 13 and making non-critical variations using 1′-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 2-{4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetamide was obtained (81%) as a colorless solid: mp 215-216° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.29 (m, 2H), 7.25-7.14 (m, 2H), 7.06-6.99 (m, 1H), 6.93-6.87 (m, 2H), 6.83-6.78 (m, 1H), 6.52 (br s, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 5.67 (br s, 1H), 5.04-4.95 (m, 2H), 4.85-4.76 (m, 1H), 4.73-4.66 (m, 1H), 4.59-4.50 (m, 2H), 4.48 (s, 2H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.9, 170.7, 161.8, 160.3, 156.7, 142.0, 132.7, 129.6, 129.0, 128.6, 123.9, 123.4, 120.1, 119.9, 118.8, 115.0, 109.1, 93.2, 80.6, 72.4, 67.1, 57.7, 43.4, 29.0; MS (ES+) m/z 443.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.CCCCCC.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=[O:28]>C1COCC1.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([CH:27]([C:26]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([F:23])[CH:25]=2)[OH:28])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COc1ccc(C=O)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c(F)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105.8 %

Procedure:
To a solution of 1-bromo-3,5-dimethoxy-benzene (5.0 g, 23.1 mmol) in THF (50 mL) was added a solution of n-butyllitium in hexane (8.7 mL, 2.5 N, 22 mmol) at −78° C. and kept for 20 min. To the mixture was added 3-fluoro-4-methoxy-benzaldehyde (3.0 g, 19.4 mmol) at −78° C. After 18 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with HCl (0.5 N, 50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent gave (3,5-dimethoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanol (6 g, 100% crude yield). The sample was used in the next step without further purification.
Reaction SMILES: COC1C=C(N[C:21]2[C:22]3[N:23]([CH:32]=[CH:33][N:34]=3)[C:24]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:25][N:26]=2)C=CC=1C(NCC1C=NC(C)=CC=1)=O.[CH:35]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[N:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)([CH3:37])[CH3:36]>>[CH:35]([N:38]1[CH2:39][CH2:40][N:41]([C:44]2[N:49]=[CH:48][C:47]([NH:50][C:21]3[C:22]4[N:23]([CH:32]=[CH:33][N:34]=4)[C:24]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:25][N:26]=3)=[CH:46][CH:45]=2)[CH2:42][CH2:43]1)([CH3:37])[CH3:36]
Reactant: CC(C)N1CCN(c2ccc(N)cn2)CC1
Reactant: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)ccc1C(=O)NCc1ccc(C)nc1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cn2)CC1

Procedure:
This compound may be prepared using the same methods as described for Compound 184, using 6-(4-isopropylpiperazin-1-yl)pyridin-3-ylamine in Step 3. LCMS: Rt=0.72 min (95%), m/z (ESI) 404 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[S:24][CH:25]=1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[S:24][CH:25]=[C:21]([CH2:20][N:5]2[C:6]3[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH:12]=[C:4]2[CH:1]2[CH2:2][CH2:3]2)[N:22]=1
Reactant: ClCc1csc(-c2ccccc2Cl)n1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2csc(-c3ccccc3Cl)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 4-(chloromethyl)-2-(2-chlorophenyl)-1,3-thiazole: 1H NMR (400 MHz, CDCl3) δ 8.18 (m, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.49 (m, 2H), 7.37 (m, 2H), 6.82 (s, 1H), 6.47 (s, 1H), 5.70 (s, 2H), 2.02 (m, 1H), 1.08 (m, 2H), 0.87 (m, 2H); MS (ES) m/z 458 (M+1) and 460 (M+1, isotope).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:27][N:28]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and methyl-phenethyl-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 512.5 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:27]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4ccc(F)cc4C3)cn2)c1
Yield: 76 %

Procedure:
The title compound was prepared in 76% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 5-fluoro-2,3-dihydro-1H-isoindole according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.08 (2H, t, J=6.0 Hz), 3.88 (2H, s), 3.92 (2H, s), 4.19 (2H, t, J=6.0 Hz), 6.98 (1H, td, J=9.6 and 2.5 Hz), 7.08 (1H, dd, J=5.5 and 2.0 Hz), 7.24 (1H, dd, J=6.7 and 3.0 Hz), 7.52 (1H, d, J=3.8 Hz), 7.80 (1H, s), 7.84 (1H, s), 8.26 (1H, s), 8.53 (1H, d, J=5.0 Hz). [M+H] Calc'd for C19H17FN4O2, 353. Found, 353.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[O:9][CH2:11][C:12]#[N:13]
Reactant: N#CCBr
Reactant: Oc1cc(I)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#CCOc1cc(I)ccc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A mixture of 2,5-diiodo-phenol (3.9 g, 11.28 mmol), bromoacetonitrile (2.03 g, 16.91 mmol) and potassium carbonate (3.11 g, 22.55 mmol) in 7 mL acetonitrile was sealed in a stoppered flask and stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chomatographed on silica gel (30%-70% CH2Cl2/hexanes) to give 2.78 g of (2,5-Diiodo-phenoxy)-acetonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc2ncccc2c1
Product: COc1cc2nccc(Oc3ccc4ncccc4c3)c2cc1OC
Yield: 46.4 %

Procedure:
Using 4-chloro-6,7-dimethoxyquinoline (90 mg) and commercially available 6-hydroxyquinoline (176 mg), reaction and purification were carried out in the same manner as described in Example 8 to obtain 62 mg of the title compound (yield: 46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[C:13](=[O:18])[NH:14][N:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[C:13](=[O:18])[N:14]([CH3:28])[N:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1[C@@H](CC(=O)c1ccn[nH]c1=O)c1ccc(Br)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: Cc1ccccc1[C@@H](CC(=O)c1ccnn(C)c1=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of (S)-4-(3-(4-bromophenyl)-3-o-tolylpropanoyl)pyridazin-3(2H)-one (293 mg, 679 μmol) in N,N-dimethylacetamide (4 mL) was added iodomethane (101 mg, 712 μmol) followed by potassium carbonate (103 mg, 746 μmol). The reaction mixture was stirred for 5½ h at room temperature and then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2, gradient heptane to heptane/ethyl acetate 1:1) produced the title compound (251 mg, 90%). White solid, MS: 411.2 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=C(F)C=2)=NOC=1C)=O)C>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Agent: CCOC(=O)c1c(-c2cccc(F)c2)noc1C
Product: Cc1onc(-c2ccc(Cl)cc2)c1CO
Yield: 65.2 %

Procedure:
As described for example 88d, 3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (373 mg, 1.4 mmol) was converted, instead of 3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (204 mg, 65%) which was obtained as a white solid. MS: m/e=224.1 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][S:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4][C@H:3]1[NH:15][C:16](=O)[CH2:17][CH3:18].[OH-].[Na+]>O1CCCC1.O>[OH:1][C@@H:2]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][S:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4][C@H:3]1[NH:15][CH2:16][CH2:17][CH3:18]
Reactant: CCC(=O)N[C@@H]1CCc2cc3c(cc2[C@H]1O)SCC3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN[C@@H]1CCc2cc3c(cc2[C@H]1O)SCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
In a 500 ml three-necked flask fitted with a magnetic stirrer and a nitrogen inlet, 2.3 g (61 mmol) of AILiH4 are suspended in 75 ml of dry tetrahydrofuran. 6.2 g (24.5 mmol) of the product obtained in Step 2 dissolved in 97 ml of dry tetrahydrofuran are slowly added at room temperature. After 18 hours' stirring at room temperature, the reaction is stopped by the addition of 1.6 ml of water, 1.3 ml of 20 % NaOH in water and finally 5.8 ml of water in succession. The reaction mixture is stirred for 0.5 hour at room temperature and then filtered. The precipitate is washed copiously with tetrahydrofuran and the flitrate is concentrated in vacuo to yield 1.37 g of the expected product in the form of a meringue, Yield: 97 %.