Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:8]([C:25]#[N:26])[C:7]1=[O:27].CSC>ClCCl.FC(F)(F)C(O)=O>[F:24][C:20]1[CH:19]=[C:18]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[NH:6][C:7](=[O:27])[C:8]=2[C:25]#[N:26])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(-c3cccc(F)c3)c3cc(OC)ccc32)c(OC)c1
Solvent: ClCCl
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 48 h

Procedure:
To a solution of 1-(2,4-dimethoxybenzyl)-4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (42 mg, 0.094 mmol) in 0.5 mL of dichloromethane and 1 mL of trifluoroacetic acid was added dimethyl sulfide (0.10 mL). After stirring for 2 days, the reaction was heated to reflux for 10 hours, then concentrated in vacuo. The crude product was triturated with EtOAc to provide the titled product as a pale yellow solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C17H11FN2O2 (M+H+): 295.0878. Found 295.0879.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.[CH2:14]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1)[CH3:15]>>[F:12][C:2]([F:1])([F:13])[C:3]1[N:4]=[CH:5][C:6]([C:7]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([O:16][CH2:14][CH3:15])=[CH:18][C:19]=2[N+:24]([O-:26])=[O:25])=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2ccc(C(F)(F)F)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-trifluoromethylnicotinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.23 (s, 1H), 9.32 (d, J=3.6, 1H), 8.83 (d, J=9.3, 1H), 8.47-8.43 (m, 1H), 7.88 (d, J=8.1, 1H), 7.76 (d, J=3.0, 1H), 7.35-7.31 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13](=[CH2:24])[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:16][OH:17].C([O-])(=O)C.[Na+].C(OCC)C>ClCCl>[CH3:24][C:13](=[CH2:12])[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH:16]=[O:17]
Reactant: C=C(C)C(CCO)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(C)C(CC=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
Solid pyridinium chlorochromate (110.24 g, 0.5 mol) was added portion-wise to a pre-cooled (−10° C.) mixture of 4-methyl-3-phenyl-4-penten-1-ol (70 g, 0.418 mol) and anhydrous sodium acetate (41.5 g, 0.5 mol) in dry dichloromethane (400 ml) under nitrogen. After 30 minutes, the reaction was warmed up to room temperature. After 4 hours, diethyl ether (1 liter) was added to the reaction. After stirring for 30 minutes, the reaction was filtered through silica gel, rinsing with diethyl ether. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1 to 5:1) followed by distillation through a 20-cm Widmer column. 24 g (yield=33%) of the desired product were obtained. B.P.=50° C./0.001 mbar.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH3:5].CS[C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19]>C(O)C>[N+:18]([CH:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([CH3:5])[N:6]1[C:7]1[CH:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)([O-:20])=[O:19]
Reactant: CC(CCN)Nc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CC1CCNC(=C[N+](=O)[O-])N1c1ccc(Cl)nc1
Temperature: 20 °C

Procedure:
A mixture of 1-amino-3-[N-(6-chloro-3-pyridyl)amino]butane (0.94 g, 0.0047 mol) (ex Example 6), 1,1-bis(methylthio)-2-nitroethene (0.78 g, 0.0047 mol) and ethanol (100 ml) was heated under reflux for 24 hours. The resulting mixture was cooled to ambient temperature (20° C.) and filtered to isolate the product 2-nitromethylene-1-(6-chloro-3-pyridyl)-6methylhexahydropyrimidine as a white solid in a yield of 0.3 g (25%), m.p. 184.5° C.
Reaction SMILES: [CH3:1][C:2]1([N+:13]([O-])=O)[CH2:5][N:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.C(O)(=O)C.ClCCl>C(OCC)(=O)C.[Fe]>[NH2:13][C:2]1([CH3:1])[CH2:5][N:4]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:3]1
Reactant: CC1([N+](=O)[O-])CN(Cc2ccccc2)C1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(N)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-methyl-3-nitro-N-benzylazetidine [the product of step 2] (3.9 g, 18.9 mmol) in ethyl acetate (370 ml) and 5% acetic acid (370 ml) is heated to reflux. Iron powder (5.25 g, 94.1 mmol) is added portion-wise every 5 minutes. After the addition is complete the reaction mixture is heated at reflux for 6 hours. The cooled reaction mixture is filtered through Hyflo, and the residue washed with ethyl acetate. The filtrate is transferred to a separating funnel and the organic layer separated and discarded. The aqueous layer is treated with 30% NaOH solution with ice cooling to give a pH of ca. 11. Dichloromethane is then added and the mixture vigorously stirred at ambient temperature for 10 minutes. This mixture is filtered through Hyfol, the filtrate transferred to a separating funnel and the organic layer is separated, dried (Na2SO4), filtered, and concentrated. The crude oily product (2.30 g, 69%) is used in the next step without further purification. 1H-NMR (CDCl3): 7.2 (m, 5H), 3.62 (s, 2H), 3.27 (d, 2H), 2.88 (d, 2H), 1.68 (bs, 2H), 1.4 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1>>[CH3:28][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)[O:27][N:26]=1
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Reactant: Cc1cc(CCCCCBr)on1
Product: Cc1cc(CCCCCOc2ccc(-c3nc4ccccc4s3)cc2)on1

Procedure:
2-{4-[[5-(3-Methyl-5-isoxazolyl)pentyl]oxy]phenyl}-benzothiazole [II; R1 and R2 =H, Het=benzothiazol-2-yl] was prepared from 5 g 2-(4-hydroxyphenyl)benzothiazole and 5.1 g 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 4: yield 6.9 g, m.p. 120-121° C. when recrystallized from triethylamine and then from isopropyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17].Cl>[N+](C1C=CC=CC=1)([O-])=O>[OH:9][C:7]1[CH:8]=[C:2]([OH:1])[C:3]([OH:4])=[CH:5][C:6]=1[C:14]([CH2:15][CH:16]([CH3:18])[CH3:17])=[O:19]
Reactant: Oc1ccc(O)c(O)c1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)CC(=O)c1cc(O)c(O)cc1O
Temperature: 25 °C
Yield: 87 %

Procedure:
In a vessel fitted with a calcium chloride tube, 12.61 g (100.0 mmol) of hydroxyhydroquinone (2) was suspended in 110 ml of nitrobenzene and stirred at room temperature. Into this, 40.0 g (300 mmol, 3.00 equivalents) of granular aluminum chloride was added piecemeal. They were further stirred for one hour and then 12.06 g (100.0 mmol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise. As the reaction mixture became a reddish purple amorphous solid 10 hours after the addition, it was mechanically crushed into fine fragments. The fine fragments were poured into 500 ml of a cold 2 M hydrochloric acid solution, stirred for 30 minutes, and extracted from ether. The ether layer was washed with water, distilled to remove the solvent, combined with a large volume of water, and distilled water under reduced pressure to remove nitrobenzene by steam distillation method. The residue of the distillation was dissolved in ether, washed with saturated brine, dried over sodium sulfate, distilled under a reduced pressure to remove ether and obtain a crude reaction product. By recrystallizing the crude product from hexane-petroleum ether (2:1), 18.3 g (yield 86.6%) of the product (7) was obtained in the form of reddish purple crystals of thin needles.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H][H].C(N(CC)CC)C.O>Cl.[Pd]>[NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
A suspension of 10.2 g of Z-Asn(Trt)-OH (20 mmol) in 120 ml of one-normal aqueous hydrochloric acid is hydrogenated in the presence of 0.5 g of a 10% palladium on charcoal catalyst at room temperature and under atmospheric pressure. After uptake of hydrogen is complete, the catalyst is filtered off and thoroughly washed with methanol, and the filtrate is concentrated under reduced pressure to a weight of 100 g. Addition of 2.8 ml of triethylamine (20 mmol) is followed by further concentration to a weight of 50 g and the crystalline precipitate is filtered off and washed with a 1:1 mixture of methanol and water and then with water until free of chloride. The H-Asn(Trt)-OH contains 0.5 mole of water and slowly decomposes above 220°.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])=[N:7][N:6]=[CH:5][C:4]=2[CH:3]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[CH:34]1([NH:37][C:38](=[O:55])[C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:40]=2)[CH2:36][CH2:35]1>O.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>[CH:34]1([NH:37][C:38](=[O:55])[C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[C:41]([C:2]3[C:11](=[O:12])[N:10]([CH3:13])[C:9]4[C:8]([C:14]5[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=5[F:21])=[N:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[CH:40]=2)[CH2:35][CH2:36]1
Reactant: Cn1c(=O)c(Br)cc2cnnc(-c3ccc(F)cc3F)c21
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(-c3ccc(F)cc3F)c2n(C)c1=O
Temperature: 100 °C

Procedure:
To a suspension of 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one (8) (80.0 mg, 0.227 mmol) in 3:1 1,4-dioxane: 1 M aq Na2CO3 (3.2 mL) was added N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (82.1 mg, 0.273 mmol) and tetrakis(triphenylphosphine)palladium (0) (21.0 mg, 0.0182 mmol). The reaction mixture was stirred and heated in a microwave at 100° C. for 55 min and then cooled to room temperature. The mixture was diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic extract was washed with 2 M Na2CO3, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography [eluting with a gradient of 40-50% B in A where the eluents were: A=CH2Cl2; B=4% MeOH in EtOAc] to give N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide as a white solid. MS (ESI, pos. ion) m/z: 447 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.52-0.60 (m, 2H), 0.64-0.73 (m, 2H), 2.21 (s, 3H), 2.85 (td, J=3.9, 7.3 Hz, 1H), 3.16 (s, 3H), 7.32-7.42 (m, 2H), 7.45-7.54 (m, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.79-7.91 (m, 2H), 8.19 (s, 1H), 8.41 (d, J=3.9 Hz, 1H), 9.45 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH:16]C(=O)C)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(C1C=CC=C2C=1NC1C(C)(CN)OCCC2=1)C.COC1C=C2C(C3CCOC(C)(CN)C=3N2)=CC=1.C1(COC2C=C3C(=CC=2)NC2C(C)(CN)OCCC3=2)C=CC=CC=1.C(C1(CN)C2NC3C(C=2CCO1)=CC=CC=3)CC.FC(F)(F)C1C=CC=C2C=1C1CCOC(C(N)C)(C)C=1N2>>[CH3:1][C:2]1([CH2:15][NH2:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Agent: CC(N)C1(C)OCCc2c1[nH]c1cccc(C(F)(F)F)c21
Agent: CC1(CN)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: CCCC1(CN)OCCc2c1[nH]c1ccccc21
Product: CC1(CN)OCCc2c1[nH]c1ccccc21

Procedure:
In the same manner but replacing N-[(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)methyl]-acetamide with an equivalent amount of another compound of formula IIa described in Examples 1 and 2, the following compounds of formula V are obtained: respectively: 8-ethyl-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine, 7-methoxy-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine, 6-phenylmethoxy-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine, 1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanamine, 1-(1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)propanamine,α-(1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-benzenemethanamine, α-(1-butyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)-benzeneethanamine,1-(6-chloro-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-ethanamine,1-(6-nitro-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)ethanamine and 1-(5-trifluoromethyl-1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-ethanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]([CH3:16])=[CH:12][C:13](O)=O>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:11]([CH3:16])([CH3:10])[CH2:12][CH2:13]2
Reactant: CC(C)=CC(=O)O
Reactant: Oc1ccc(Cl)c(O)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CCc2cc(Cl)c(O)cc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The desired 6-chloro-2,2-dimethylchroman-7-ol was synthesized from 4-chlororesorcinol as follows. A mixture of 3,3-dimethylacrylic acid (7.0 g) and 4-chlororesorcinol (10 g) in Eaton's reagent (50 mL) was stirred at ambient temperature for 16 h. At the end, the mixture was poured over ice and the precipitate was filtered, dried and crystallized from aqueous methanol to provide 6-chloro-7-hydroxy-2,2-dimethyl-2,3-dihydro-4H-chomen-4-one (8.7 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([NH2:16])[CH:12]=[CH:11][CH:10]=2>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[CH3:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([N:16]=[C:1]=[O:2])[CH:12]=[CH:11][CH:10]=2
Reactant: O=C(Cl)Cl
Reactant: Cc1cc2c(N)cccc2cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc2c(N=C=O)cccc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of phosgene (20% in toluene, 2.9 mL, 5.5 mmol) of dichloromethane (30 mL) was cooled to 0° C. and treated dropwise with a solution of 4-dimethylaminopyridine (1.43 g, 11.7 mL) in dichloromethane (15 mL). A thick white suspension formed. A solution of 3-methyl-isoquinolin-5-ylamine (0.79 g, 5 mmol) in tetrahydrofuran (20 mL) was then added dropwise to this suspension. The reaction mixture was allowed to warm to ambient temperature and stirred overnight, the solvent was removed under reduced pressure, and the residue titurated with 50 mL of diethyl ether to give an approximately 0.1 M solution of 3-methyl-5-isocyanato-isoquinoline.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C(O)(C)C>C1COCC1.O>[O:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:23]([C:22]3[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[OH:24])=[CH:3][C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: COc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(O)c2ccc3c(c2)OCCO3)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 6-bromo-2,3-dihydro-benzo[1,4]dioxine (1.66 g, 7.7 mmol) and dry THF (20 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (2.9 mL, 7.4 mmol) and stirred for 20 min. Then a mixture of 4-methoxy-benzaldehyde (0.90 g, 6.6 mmol) in dry THF (10 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.4 mL, 44 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic phases were washed with water (2×30 mL), dried over MgSO4 and concentrated to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-methoxy-phenyl)-methanol as an oil (2.04 g, 102% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Cl)[CH:9]=1)[C:5]#[N:6].ClCl.C[O-].[Na+].C[O:17]C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:17])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Cl)c1
Reactant: COC
Agent: C[O-]
Agent: ClCl
Agent: [Na+]
Product: N#Cc1cc(O)cc(Cl)c1

Procedure:
The requisite phenols utilized in the condensation with 15 or 18b were prepared as depicted in SCHEME 3. Dibromofluorobenzene (20a) was treated with sodium methoxide resulting in displacement of the fluorine substituent to afford 20b. Monometallation and formylation of the resulting lithium salt with DMF afforded 21. Conversion of the formyl group into a difluoromethyl group was effected with DAST. Demethylation of the methyl ether afforded the requisite phenol 23. 3-Chloro-5-hydroxy-benzonitrile (24c) was prepared form 3,5-dichloro-benzonitrile by displacement of a chlorine substitutent with sodium methoxide and demethylation of the resulting ether to afford 24c.
Reaction SMILES: Cl.Cl[C:3]1[NH:4][C:5](=[O:14])[C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:13][C:12]1[C:6]2[C:5](=[O:14])[NH:4][C:3]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:8][C:7]=2[N:9]=[CH:10][CH:11]=1
Reactant: OCCCCCc1ccccc1
Reactant: Cc1ccnc2nc(Cl)[nH]c(=O)c12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccnc2nc(OCCCCCc3ccccc3)[nH]c(=O)c12
Temperature: 120 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
2-Chloro-5-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride (36 mg, 155 μmol) was dissolved in DMSO (0.8 ml). Molecular sieves 4Å, 5-phenyl-1-pentanol (80 μl, 465 μmmol) and potassium tert-butylate (35 mg, 310 μmol) were added and the suspension was stirred at 120° C. for 48 h under an argon atmosphere. The molecular sieves were filtered off, the filtrate was poured onto ice water/isopropyl acetate 1/1, the layers were separated and the aqueous layer was extracted two times with isopropyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, isopropyl acetate/heptane) to give 5-methyl-2-(5-phenyl-pentyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one (16 mg, 50 μmol; 32%) as yellow crystals. MS: m/e=324.4 [M+H+].
Reaction SMILES: C([O-])(=[O:3])C.[K+].Br[CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:31][CH3:32])=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[CH:17]=[C:16]2[NH:22][C:23]1[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=1[Cl:30]>>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[NH:22][C:16]1[C:15]2[C:20](=[C:11]([O:10][CH2:9][CH2:8][CH2:7][OH:3])[C:12]([O:31][CH3:32])=[CH:13][CH:14]=2)[O:19][C:18](=[O:21])[CH:17]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCBr
Reactant: CC(=O)[O-]
Agent: [K+]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCO

Procedure:
The title compound can be prepared from potassium acetate and 8-(3-bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 30) following the procedures outlined in Examples 52 & 42. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.44 (t, 1H), 4.07 (t, 2H), 3.92 (s, 3H), 3.57 (q, 2H), 1.82 (m, 2H); MS (ESI): 410.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N+:17]([O-])=O)=[C:13]([CH:16]=2)[NH:14][CH3:15])=[C:4]([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:17])=[C:13]([NH:14][CH3:15])[CH:16]=2)=[C:4]([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:3]=1
Reactant: CNc1cc(Sc2ccc(Cl)cc2Cn2cncn2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNc1cc(Sc2ccc(Cl)cc2Cn2cncn2)ccc1N

Procedure:
5-[4-Chloro-2-(1H-1,2,4-triazol-1-ylmethyl)phenylthio]-N-methyl-2-nitroaniline (0.14 g) from Example 70 was dissolved in acetic acid (2ml), followed by gradual addition of zinc powder (120 mg) at room temperature. After the addition, ethyl acetate was added to filter off insoluble materials, and to the filtrate was added saturated sodium hydrogen carbonate solution carefully for separation. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, 4-[4-chloro-2-(1H-1,2,4-triazol-1-ylmethyl)phenylthio]-2-methylaminoaniline was obtained as is the crude product.
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22]([N:23]=[C:24]4[CH2:30][CH2:29]CC[CH2:26][C:25]=24)=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=1.ClCCC[O:35]C1C=CC(C2N3C(=CC=N3)N=C3C=2CCC3)=CC=1.O[C@@H]1CCNC1>>[N:19]1[N:18]2[C:22]([N:23]=[C:24]3[C:25](=[C:17]2[C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][C@@H:6]([OH:35])[CH2:2]4)=[CH:12][CH:13]=2)[CH2:26][CH2:29][CH2:30]3)=[CH:21][CH:20]=1
Reactant: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1
Agent: O[C@@H]1CCNC1
Product: O[C@@H]1CCN(CCCOc2ccc(-c3c4c(nc5ccnn35)CCC4)cc2)C1

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-[4-(3-chloro-propoxy)-phenyl]-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 3-(R)-hydroxy-pyrrolidine provided the title compound.