Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]=[C:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:34])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N=C1CCN(c2ccncc2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
A solution of 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylideneamino]-2-piperazinone (120 mg) in trifluoroacetic acid (1 ml) was combined with triethylsilane (60 mg) and stirred at 50° C. for 4 hours. The reaction mixture was concentrated and the residue was combined with an ice-cooled 1 N aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and then concentrated. The residue obtained was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from acetone to obtain the title compound (88 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1C=CC=C[C:6]=1[OH:11])[CH2:2]CC.[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Cl)(Cl)(Cl)=O>C(Cl)CCl>[CH3:12][NH:13][C:14](=[O:15])[O:11][CH2:6][CH2:5][CH2:1][CH3:2]
Reactant: CCOC(=O)NC
Reactant: CCCCc1ccccc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCCOC(=O)NC

Procedure:
To a solution of 2-sec butylphenol (1.5 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) in ethylene dichloride (6 ml) was added phosphoryl chloride (0.77 g, 0.05 mole) and the reaction mixture was refluxed under stirring for twenty hours. It was poured onto ice-cold water. The organic layer separated and aqueous layer was extracted with dichloroethane. The combined organic layer was washed with water, dried (Na2SO4) and distilled to give liquid residue, which was further purified by distillation to give 2-sec butyl N-methylcarbamate of the formula (III) [96% by GLC, DV-101 (3%), 150° C., nitrogen, 30 ml/min.] as a liquid, b.p. 110° C. (vap.)/4 mm; IR: 3320 (N--H), 1730 (--COO--), 1535,1490 and 750 (aromatic); PMR (CDCl3, 90 MHz): 0.81 (3H,t, primary methyl of side chain, 1.58 (2H, m, methylene protons of side chain), 2.88 (4H, doublet overlapping a multiplet, NH--CH3 and benzylic proton), 4.97 (1H, br s, N--H) and 6.95 to 7.25 (4H, m, aromatic).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:18]([O-:20])=[O:19])[CH:8]=2)[N:3]=1.O.[NH2:22][NH2:23]>>[N+:18]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][NH2:23])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:20])=[O:19]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc2nc(Cl)cc(-c3ccccc3)c2c1
Solvent: O
Product: NNc1cc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-nitro-4-phenylquinoline is reacted at reflux with hydrazine hydrate to give 6-nitro-4-phenyl-2-hydrazinoquinoline.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH2:15][CH2:16][C:7]=2[C:6]([C:17]([O:19]C)=[O:18])=[CH:5]1.O.O.[Li]>C1COCC1.O.CO>[F:22][C:2]([F:1])([F:21])[CH2:3][N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH2:15][CH2:16][C:7]=2[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1
Reactant: COC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2

Procedure:
To a solution of methyl 1-(2,2,2-trifluoroethyl)-4,5-dihydro-1H -pyrrolo[2,3-f]isoquinoline-3-carboxylate E3 (0.13 mmol) in THF/water/MeOH 8:1:1 lithium hydrate monohydrate (0.39 mmol) was added. The reaction mixture was refluxed for 8 h then the solvent was removed under reduced pressure. The residue was dissolved in water, the solution was neutralized with diluted aq potassium hydrogenosulphate and extracted with DCM/water 9:1. The organic layer was dried (Na2SO4) and evaporated to dryness. Trituration with diethylether provided the title compound. The aqueous layer was concentrated and the residue was cromatographed on silica gel (eluant: DCM/MeOH/30% NH3 90:9:1). The title compound was isolated in 60% overall yield. ESI (+) MS: m/z 297 (MH+). MS (ES−) 295. 1H NMR: 5.43 (q, J=8.98, 2H), 7.70 (d, J=5.73, 1H), 7.76 (s, 1H), 8.48 (d, J=5.61, 1H), 8.51 (s, 1H), 12.32 (s, 1H).
Reaction SMILES: [Br-:1].[Mg+2].[Br-].CS([CH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)(=O)=O>C(OCC)C>[Br:1][CH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1
Reactant: [Br-]
Reactant: CC1(C)OCC(CCS(C)(=O)=O)O1
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C)OCC(CCBr)O1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Magnesium bromide etherate (40 g, 130 mmol) and a stir bar were added to a 2000 mL round bottom flask and flushed with nitrogen. A solution of 4-(2-methanesulfonylethyl)-2,2-dimethyl-1,3-dioxolane (I) (17.5 g, 78 mmol) in anhydrous diethyl ether (900 mL) was added via canulla, and the suspension stirred overnight. The ether was first decanted into a beaker. Water (200 mL) and ether (300 mL) were added to the precipitate and stirred for 5 minutes. The precipitate was dissolved, and the ether phase was then collected and added to the ether solution from the reaction. The organic phase was then washed, concentrated to about 500 mL, washed with water, dried over anhydrous Mg2SO4, filtered, and concentrated to yield a yellow oil (16.0 g). This was purified by flash chromatography to yield 10.6 g of product (50.7 mmol, 65%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.Cl.[NH2:18][CH:19]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:20]1[CH:21]=[C:22]([P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=1.CCN(CC)CC>O=S(Cl)Cl.C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:18][CH:19]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:20]2[CH:21]=[C:22]([P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1cccc(C(N)c2ccc(OC)cc2)c1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1cccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
The 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h, (500 mg, 2.3 mmol) was dissolved in SOCl2 (10 ml), the mixture was stirred at RT for 3 hours, then concentrated under vacuo. The residue was dissolved with 20 ml DCM, and dropwise to a solution of diethyl 3-(amino(4-methoxyphenyl)methyl)phenylphosphonate hydrochloride (5-d, 802 mg, 2.30 mmol) and Et3N (464 mg, 4.6 mmol) in DCM (30 ml) at 0° C., the mixture was stirred at room temperature overnight. Then added water, the water phase was concentrated under vacuo and purified on silica gel chromatography to provide the product, 5-e, (990 mg, 78.4%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:60][N:61]1[CH2:66][CH2:65][N:64]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH2:63][CH2:62]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(Br)cc32)cc1
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(N4CCN(C)CC4)cc32)cc1
Temperature: 100 °C
Yield: 73.8 %

Procedure:
A 250 mL round bottom flask was loaded with 6-Bromo-1-(toluene-4-sulfonyl)-1H-indole (4 g, 11.4 mmol), Cs2CO3 (7.4 g, 22.8 mmol), Pd2dba3 (0.104 g, 0.114 mmol), RuPHOS (0.106 g, 0.23 mmol), Toluene (150 mL), N-Methyl piperazine (1.9 mL, 17.2 mol), evacuated and flushed with nitrogen. Next the reaction flask was heated at 100° C., over the weekend. Analysis at this point showed that most of the starting material had converted to the product. After cooling to room temperature, the solution was diluted with EtOAc (150 mL), filtered through a pad of celite, washed with additional EtOAc (150 mL) and was evaporated. The resulting oil was chromatographed on silica gel to give the product as a thick brown oil (which crystallized on standing), 3.1 g, (73.8% yield).
Reaction SMILES: ClC1C=CC(C(N)C(C2CCCCC2)N)=CC=1.Cl.C(OC1C=C(OC)C=CC=1C(=N)OCC)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[NH:46][C:45]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:44][CH:43]2[CH2:58][CH:59]2[CH2:63][CH2:62][CH2:61][CH2:60]2)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[NH:46][C:45]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:44][CH:43]2[CH:58]2[CH2:59][CH2:63][CH2:62][CH2:61][CH2:60]2)=[CH:38][CH:37]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: CCOC(=N)c1ccc(OC)cc1OCC
Agent: Cl
Agent: NC(c1ccc(Cl)cc1)C(N)C1CCCCC1
Product: CCOc1cc(OC)ccc1C1=NC(C2CCCCC2)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-4-cyclohexyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-2-cyclohexyl-ethane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 413.1993, calculated for C24H30N2O2Cl [(M+H)+]413.1991.
Reaction SMILES: O[C:2](C(F)(F)F)=O.[CH2:8]([N:10]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:11]1[C:12]([CH3:25])=[C:13]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:9].C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:8]([N:10]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:2])[CH2:28][CH2:27]1)[C:11]1[C:12]([CH3:25])=[C:13]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:9]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCNCC1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 60 h
Yield: 28 %

Procedure:
To a stirred solution of methyl 3-[ethyl(piperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoate TFA salt (crude material, 5.30 g, 12.0 mmol) in CH2Cl2 (150 mL) and AcOH (10 mL) was added formaldehyde (15 mL, 44% aqueous solution) and sodium triacetoxyborohydride (6.40 g, 30.0 mmol). The reaction mixture was stirred at 23° C. for 2.5 days. Then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2 heptane/EtOAc=2/1) to give the titled compound as oil (1.20 cg, 28% yield). 1H-NMR (400 cMHz, CDCl3) δppm; 7.81 (br. s., 1H), 7.45 (d, J=2.0 Hz, 1H), 3.92 (s, 3H), 3.10 (q, J=7.0 Hz, 2H), 2.83 (m, 2H), 2.66-2.77 (m, 1H), 2.54 (s, 3H), 2.24 (s, 3H), 1.84-1.94 (m, 2H), 1.63-1.78 (m, 4H), 0.86 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 359.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].C(N(CC)CC)C.[C:40](Cl)(=[O:44])[CH:41]([CH3:43])[CH3:42]>ClCCl>[C:40]([NH:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4])(=[O:44])[CH:41]([CH3:43])[CH3:42]
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C(C)C)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a stirred solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (80 mg) and triethylamine (22.4 mg) in dichloromethane (1 ml) was dropwise added isobutyryl chloride (19.9 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[3-[N-(isobutyrylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (69 mg) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C.Cl>O1CCCC1>[CH3:14][O:15][C:16](=[O:17])[NH:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C2CC2)nc(N)n1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(C)cc(C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 53.7 g of 2-amino-4-cyclopropyl-6-methylpyrimidine in 1000 ml of tetrahydrofuran is added portionwise, under a nitrogen atmosphere, 42.8 g of 50% sodium hydride while cooling the reaction flask in an ice-water bath. After stirring one hour at 25° C. 58.5 g of dimethylcarbonate is added dropwise at 5° to 25°. The suspension is stirred about 16 hours at ambient temperatures, then 80 ml of concentrated hydrocloride acid is added dropwise under a nitrogen atmosphere while maintaining a reaction temperature of 20° to 25° with external ice-bath cooling. The suspension is stirred 0.5 hour, filtered, and the filtrate is dried over sodium sulfate and concentrated in vacuo to give the subject compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:15][N:2]([CH2:3][C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:12]=[CH:13][CH:14]=1)[CH3:1]
Reactant: COC(=O)c1cccc(C(=O)N(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(CO)c1
Yield: 55.7 %

Procedure:
3-(N,N-Dimethylamino carbonyl)benzoic acid, methyl ester (36 g) in dry tetrahydrofuran was added to lithium aluminium hydride (16.6 g) in dry tetrahydrofuran. The reaction mixture was heated at 60° for 3 hours, cooled and treated with water. The solvent was removed and the residue treated with dilute hydrochloric acid. The mixture was basified with sodium hydroxide and extracted with chloroform. The organic extracts were dried and distilled to give an oil (16 g) b.p. 95°-100° (0.1 mm). TLC silica/methanol Rf 0.57.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1)(=[O:28])=[O:27]
Reactant: CN1CCC2(CC1)CC(=O)c1cc(N)ccc1O2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCC2(CC1)CC(=O)c1cc(NS(C)(=O)=O)ccc1O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 419 %

Procedure:
3,4-Dihydro-6-amino-1'-methyl-spiro[2H-1-benzopyran-2,4'-piperidin]-4-one (5.6 g, 0.0027 mol) was stirred in methylene chloride (50 ml) and pyridine (16 ml) at room temperature under a nitrogen atmosphere as methanesulfonyl chloride (2.7 ml, 0.035 mol) was added dropwise over several minutes. Some gum separated so additional pyridine (25 ml) was added. The mixture was stirred at ambient temperature for 16 hours. The methylene chloride and pyridine were removed in vacuo and the residue was taken up in saturated NaHCO3 (150 ml) and methylene chloride (150 ml). The methylene chloride layer was separated and the aqueous phase was again extracted with methylene chloride. The combined extracts were washed with sodium bicarbonate, dried filtered and concentrated in vacuo. The residual mixture was chromatographed on silica gel (500 g) using 15% methanol/chloroform to yield 3.67 g (50%) of product.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([NH:38][C:39]([NH:41][C:42]2[CH:46]=[C:45]([CH3:47])[O:44][N:43]=2)=[O:40])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:37]=[C:36]([NH:38][C:39]([NH:41][C:42]2[CH:46]=[C:45]([CH3:47])[O:44][N:43]=2)=[O:40])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][CH2:30][CH2:31][O:32][CH3:33])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(CCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)nc1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Compound 182 (0.17 g, 0.26 mmol) was suspended in dichloromethane (50 mL) and TFA (1 mL) was added. This solution was stirred for 1 h then the mixture was concentrated. The residue was partitioned between ethyl acetate and water, washed with 3M NaOH and brine, then dried over anhydrous MgSO4, filtered and concentrated. The residue was triturated with diethyl ether and dried in vacuo to afford title compound 183 (0.125 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.74 (s, 1H); 9.33 (s, 1H); 8.52 (d, J=5.5, 1H): 8.51-8.50 (m, 1H); 8.29 (s, 1H); 8.18 (d, J=8.0, 1H): 7.81 (dd, J=8.2, 2.2, 1H); 7.74 (J=12.9, 2.5, 1H); 7.46 (t. J=9.0, 1H); 7.30-7.27 (m, 1H); 6.66 (d, J=5.5, 1H); 6.55 (s, 1H); 3.37 (t, J=5.7, 2H); 3.22 (s, 1H); 2.82-2.75 (m, 4H); 2.68 (t, J=5.5, 2H); 2.37 (s, 3H). LRMS (M+H): 563.5.
Reaction SMILES: C([O:9][C:10](=[CH:15][C:16]1[CH:24]=[C:23]([CH3:25])[C:22]2[C:18](=[CH:19][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:21]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])(=O)C1C=CC=CC=1.CO.[H][H].O.[OH-].[Li+]>O.[Pd]>[OH:9][CH:10]([CH2:15][C:16]1[CH:24]=[C:23]([CH3:25])[C:22]2[C:18](=[CH:19][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[N:21]=2)[CH:17]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(=Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(CC(O)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A Parr bottle was charged with 1-methoxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxoprop-2-en-2-yl benzoate (1.0 g, 2.14 mmol), methanol (15 mL), and palladium (10% on charcoal, 100 mg). The Parr shaker was pressurized to 60 psi of hydrogen and shaken for 6 h. The reaction was filtered through celite and concentrated. The resulting residue was dissolved in tetrahydrofuran (8 mL) and methanol (8 mL) and cooled to 0° C. To this was added a solution of lithium hydroxide monohydrate (358 mg, 8.54 mmol) in water (8 mL). The reaction was stirred at 0° C. for 1 h, then at room temperature for 2 h. The reaction was concentrated, dissovled in water, cooled to 0° C., and acidified with 1M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2×). The organics were washed with a minimum of brine, dried over magnesium sulfate, and concentrated. Column chromatography (5% to 10% methanol/dichloromethane) gave 340 mg (45%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) 8-0.04 (s, 9H), 0.93 (m, 2H), 2.53 (s, 3H), 2.92 (m, 1H), 3.19 (m, 1H), 3.61 (m, 2H), 4.46 (bs, 1H), 5.68 (s, 2H), 6.93 (s, 1H), 7.31 (bs, 1H), 7.94 (bs, 1H). Mass spec.: 351.36 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[F:30])=[CH:22][C:21]([NH2:31])=[C:20]([NH2:32])[N:19]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[N:19]=[C:20]2[NH:32][C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[N:31][C:21]2=[CH:22][C:23]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[F:30]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2ccncc2Cl)nc1N
Product: Fc1ccc(-c2nc3cc(-c4ccncc4F)c(-c4ccncc4Cl)nc3[nH]2)cc1

Procedure:
Following the same protocol as in Example 2, but using 4-fluorobenzoylchloride and 3-chloro-3″-fluoro-4,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 8), the title compound was obtained as a white solid (13 mg, 12%).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:13][C@H:14]1O[C@@H](P(OCC)(OCC)=O)CC1>CN(C=O)C>[CH2:13]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:14]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CCOP(=O)(OCC)[C@H]1CC[C@@H](CBr)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a stirring suspension of thymine (551 mg, 3.32 mmol) in dry DMF (3 mL) was added sodium hydride (60% oil dispersion, 133 mg, 3.32 mmol). After stirring the mixture for 30 min at room temperature, a solution of cis-5-bromomethyl-2-diethoxyphosphinoyl-tetrahydrofuran (example 66) (500 mg, 1.66 mmol) in DMF (3 mL) was added via cannula. The mixture was then stirred at 90° C. for 15 h after which the mixture was cooled and quenched with saturated ammonium chloride (5 mL). The volatiles were removed under vacuo and the residue was dissolved in a mixture of dichloromethane (20 mL) and water (10 mL). The mixture was filtered and the aqueous layer was collected and extracted with dichloromethane (2×20 mL). The combined extracts were then washed with brine (20 mL), dried (MgSO4) and concentrated to dryness. Purification by chromatography eluting with EtAc, 5% MeOH in EtAc then 10% MeOH in EtAc yielded first N1 -ethyl thymine (102 mg, 40%) and then the title compound as an oil (126 mg, 22%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([C:12]([O:14]C)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH:7]1([C:12](=[O:14])[CH2:25][C:24]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1CCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCCC1)c1ccc(C(F)(F)F)cc1
Yield: 66.3 %

Procedure:
1.97 kg of potassium tert-butoxide, 2.26 kg of methyl cyclopentanecarboxylate, 1.66 kg of p-trifluoromethylacetophenone and 36 g of 18-crown-6 ether were refluxed in 18 liters of tetrahydrofuran for 4 hours. Quenching of the reaction was carried out using 16 liters of 10% strength hydrochloric acid at room temperature. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution. After distilling off the solvent, the residue was distilled in an oil-pump vacuum at 1.5 mbar. 1.664 kg of 1-cyclopentyl-3-(4-trifluoromethylphenyl)propane-1,3-dione resulted as an oil, which crystallized completely on allowing to stand.