Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16](=O)[NH:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[I:19])=[CH:5][CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)=[C:10]([I:19])[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccc(-c2c(I)oc3nc[nH]c(=O)c23)cc1
Product: CCc1ccc(-c2c(I)oc3ncnc(Cl)c23)cc1

Procedure:
Stir a suspension of 1.4 g (85% purity, 3.3 mmol) of 5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidin-4(3H)-one in 20 ml (32.9 g, 214.6 mmol) of phosphoryl chloride under reflux for one hour. After concentrating under reduced pressure, add ice-cold water and dichloromethane to the residue. Dry the organic phase over sodium sulphate and filter. Concentrate the filtrate under reduced pressure and dry. 1.0 g (70% purity, 57% of theory) of the target compound is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)[CH3:3].[NH2:19][C:20]1[N:25]=[C:24]([NH2:26])[C:23]([C:27]#[N:28])=[C:22](Cl)[N:21]=1.CCN(CC)CC>C(#N)C>[NH2:19][C:20]1[N:25]=[C:24]([NH2:26])[C:23]([C:27]#[N:28])=[C:22]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH3:3])[N:21]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(O)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CC(O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)azetidin-3-ol (75 mg, 0.304 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (62.0 mg, 0.365 mmol) and Et3N (0.085 mL, 0.61 mmol) in acetonitrile (2 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The crude product was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (5 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.40 (m, 4 H), 3.47-3.58 (m, 1 H), 3.67-3.75 (m, 1 H), 3.75-3.80 (m, 4 H), 4.05-4.14 (m, 1 H), 4.20-4.33 (m, 1 H), 4.51-4.63 (m, 1 H), 5.40-5.53 (m, 1H), 5.57-5.68 (m, 1 H), 6.38-6.53 (m, 3 H), 6.54-6.66 (m, 2 H), 6.76-6.86 (m, 1 H), 7.10-7.20 (m, 1 H), 7.36-7.46 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H21N9O, 380; found 380.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]45[CH2:24][CH:23]4[CH2:22][NH:21][CH2:20]5)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][CH2:26]N(C(C)C)C(C)C.C(I)C>CN(C=O)C>[CH2:25]([N:21]1[CH2:22][CH:23]2[C:19]([C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:11][CH2:12][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9]4)=[CH:14][CH:15]=3)([CH2:24]2)[CH2:20]1)[CH3:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc(N2CCN(c3ccc(C45CNCC4C5)cc3)CC2)cc1
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CC2CC2(c2ccc(N3CCN(c4ccccc4)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of trihydrochloride salt of 1-(4-(4-phenylpiperazin-1-yl)phenyl)-3-azabicyclo[3.1.0]hexane (0.92 g, 2.19 mmol) in dry DMF (6 mL) was added DIPEA (1.21 g, 6.44 mmol)) followed by addition of ethyl iodide (0.197 mL, 2.4 mmol). The reaction was stirred at r.t. for 3 h under argon. After completion of reaction as confirmed by TLC, crude compound was extracted with ethyl acetate (60 mL) and was given water washings (3×30 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed in vacuo to afford the crude compound which was purified by column chromatography (silica gel 0.8:9.2 MeOH:DCM) to afford pure title compound (0.61 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[N:17][CH:18]=1)[N:9]=[C:8]([C:26](OCC)=[O:27])[C:7]2=S.[NH:32]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[OH:40])[NH2:33].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[N:17][CH:18]=3)[N:9]=[C:8]3[C:26](=[O:27])[N:32]([C@@H:34]4[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]4[OH:40])[N:33]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(-c3ccc(C)nc3)nc2)c2c(Cl)cccc2c1=S
Reactant: NNC1CCCCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(Cn3nc4c(=O)n([C@@H]5CCCC[C@H]5O)nc-4c4cccc(Cl)c43)cn2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 8-chloro-1-[(6′-methyl-2,3′-bipyridin-5-yl)methyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate (26 mg, 0.0058 mmol), (±)-2-hydrazinylcyclohexanol (19 mg, 0.14 mmol, 2.5 equiv) and potassium carbonate (24 mg, 0.17 mmol, 3 equiv) were combined in dimethoxyethane (1 mL) and placed into an oil bath preheated to 90° C. for 90 minutes. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed once with water and brine. The organic layer was dried sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; chloroform:methanol), providing the titled compound as a deep red solid: 1H-NMR (400 MHz, CDCl3) δ 9.02 (1H, br s), 8.56 (1H, s), 8.21 (1H, d, J=9.1 Hz), 8.16 (1H, d, J=10.9 Hz), 7.65 (2H, d, J=7.5 Hz), 7.56 (1H, d, J=9.2 Hz), 7.43 (2H, t, J=7.5 Hz), 7.27-7.21 (1H, m), 6.33 (2H, s), 4.34-4.25 (1H, m), 4.11-4.02 (1H, m), 2.6 (3H, s), 2.26-2.17 (1H, m), 2.07-2.00 (1H, m), 1.92-1.79 (2H, m), 1.68-1.56 (2H, m), 1.52-1.39 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 501.1812 [(M+H)+; calculated for C27H25ClN6O2: 501.1800].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26]([NH:28][NH:29][C:30](=O)[C:31]([F:34])([F:33])[F:32])=O)=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26]1[S:45][C:30]([C:31]([F:34])([F:33])[F:32])=[N:29][N:28]=1
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)NNC(=O)C(F)(F)F)c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(F)(F)F)s3)c2)cc1
Yield: 59.8 %

Procedure:
A solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-N′-(2,2,2-trifluoroacetyl)-[1,1′-biphenyl]-2-carbohydrazide (502 mg) and Lawesson's reagent (825 mg) in THF (10 mL) was stirred at 80° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (299 mg) as a pale-yellow solid. The present compound was used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:15]3[C:25](=[O:26])[NH:24][CH:23]=[CH:22][C:16]=3[N:17]=[C:18](SC)[N:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[NH2:36]>>[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[NH:36][C:18]1[N:19]=[C:14]([NH:13][C:5]2[CH:4]=[C:3]([C:2]([F:28])([F:27])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[C:15]2[C:25](=[O:26])[NH:24][CH:23]=[CH:22][C:16]=2[N:17]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CSc1nc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1
Product: N[C@@H]1CCCC[C@H]1Nc1nc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(=O)[nH]ccc2n1

Procedure:
The title compound was prepared as described in Example 1g by starting from 4-(3,5-bis(trifluoromethyl)phenylamino)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (100 mg, 0.24 mmol) and (±)-trans-1,2-diamino cyclohexane and continuing until the reaction yielded the title compound, 2-((1R,2R)-2-aminocyclohexylamino)-4-(3,5-bis(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one. MS m/z: 487 (M+1)+ 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25-1.97 (m, 10H), 6.10 (d, J=7.2 Hz, 1H), 7.41-7.44 (m, 3H), 7.41-7.76 (m, 4H), 8.47 (s, 2H), 12.49 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].O.[CH2:34]1[CH2:38]O[CH2:36][CH2:35]1>>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:19]([CH:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:23][CH:22]([N:21]5[CH2:38][CH2:34][CH2:35][CH2:36]5)[CH3:27])[CH:7]=4)=[CH:10][CH:11]=3)[CH2:16]2)=[O:20])[CH:27]=[CH:26][CH:25]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)c1
Agent: [Cl-]
Solvent: O
Product: CC(CNc1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-[(2-aminopyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.50 g, 3.64 mmol) in THF (36 mL) at 0°, was added TEA (1.02 mL, 7.29 mmol) and then 2-chloropropanyoyl chloride (0.39 mL, 4.01 mmol) dropwise. The reaction was allowed to warm to rt and stir for 18 h. Water was added and the mixture was extracted with EtOAc (2×). The organic solutions were combined, washed with water, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give N-(3tert-butylphenyl)-7-({2-[(2-pyrrolidin-1-ylpropanyl)amino]pyridin-4yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-275 as a pale yellow solid (1.37 g, 74.9%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>O>[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:20]=[O:21])=[CH:10][NH:11]2
Reactant: Clc1cccc2[nH]ccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cccc(Cl)c12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
During a period of five minutes 2.3 grams (0.015 mole) of phosphorus oxychloride was added dropwise to 10 mL of N,N-dimethylformamide. The solution was stirred for 30 minutes and then cooled in an ice bath. To this was added dropwise a solution of 2.0 grams (0.013 mole) of 4-chloroindole in 3 mL of N,N-dimethylformamide. Upon completion of the addition the ice bath was removed, and the reaction mixture was warmed to ambient tempeature, where it stirred for 1.5 hours. After this time the reaction mixture was warmed to 40° C., where it was stirred for 30 minutes, and then poured onto 50 grams of ice. A solution of 5.9 grams (0.146 mole) of sodium hydroxide in 20 mL of water was added during a 2-3 minute period, after which the mixture was heated to reflux and then cooled to ambient temperature. The cooled mixture was poured into 500 mL of water, stirred at ambient temperature for about 18 hours, and then filtered to collect a solid that had precipitated. The solid was washed with three portions of water and then dissolved in ethyl acetate. The ethyl acetate solution was subjected to column chromatography on silica gel with 1:1 ethyl acetate:hexane as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.4 grams of 4-chloro-3-formylindole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N+:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]([CH2:31][CH2:32]Br)[CH2:26][CH2:25][CH2:24]2)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]([CH2:31][CH2:32][N:15]1[CH2:14][CH2:13][CH:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)[CH2:17][CH2:16]1)[CH2:26][CH2:25][CH2:24]2)([O-:20])=[O:19]
Reactant: COc1ccc(C2CCNCC2)cc1OC
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCC2CCBr
Agent: Cl
Product: COc1ccc(C2CCN(CCC3CCCc4cc([N+](=O)[O-])ccc43)CC2)cc1OC

Procedure:
Analogously to Example 5, reaction of 4-(3,4-dimethoxyphenyl)piperidine hydrochloride with 2-(6-nitrotetralin-1-yl)ethyl bromide gives 1-(2-(6-nitrotetralin-1-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine.
Reaction SMILES: [F:1][C:2]([F:16])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:3]([O-:5])=O.[Na+].[CH3:18][N:19]1[CH:23]=[C:22]([C:24]2[N:29]=[N:28][C:27]([NH:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=2)[CH:21]=[N:20]1.N1C=CN=C1.S(Cl)(Cl)=O>C(#N)C>[F:16][C:2]([F:1])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:3]([N:28]1[N:29]=[C:24]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[CH:25]=[CH:26]/[C:27]/1=[N:30]\[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:5]
Reactant: Cn1cc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)cn1
Reactant: O=C([O-])C(F)(F)c1ccc2ncccc2c1
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cn1cc(-c2cc/c(=N\NC(=O)OC(C)(C)C)n(C(=O)C(F)(F)c3ccc4ncccc4c3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
900 mg (3.67 mmol) of sodium difluoro(quinolin-6-yl)acetate was dissolved in acetonitrile (27 mL). 1.17 g (4.04 mmol) of tert-butyl 2-[6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl]hydrazinecarboxylate was added and 300 mg (4.41 mmol) of 1H-imidazole was added at once. 0.561 mL (7.71 mmol) of thionyl chloride was added over 5 minutes at room temperature. The mixture was stirred for 2 hours at room temperature, giving tert-butyl (2E)-2-{2-[difluoro(quinolin-6-yl)acetyl]-6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-ylidene}hydrazinecarboxylate. Then, 0.722 mL (11.0 mmol) of methanesulphonic acid was added at room temperature and stirred for 16 h. The resulting solids were filtered off under argon atmosphere, yielding 6-{1,1-difluoro-2-[(6E)-6-hydrazono-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-1(6H)-yl]-2-oxoethyl}quinoline and used as such in the next step.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:33]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=401.1 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COC(=O)CBr
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1=C(COCCNCC(=O)OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 40.7 %

Procedure:
A solution of methyl bromoacetate (1.53 g) in acetonitrile (20 ml) was added dropwise over 30 minutes to a stirred, refluxing mixture of 2-[(2-aminoethoxy)methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (5.01 g) and potassium carbonate (2.76 g) in acetonitrile (60 ml). The mixture was then heated under reflux for 3 hours, filtered, and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (Na2SO4), and evaporated. The residue was chromatographed on silica (t.l.c. grade Merck Kieselgel 60H, [Trade Mark] 40 g) eluting with dichloromethane plus 0-3% methanol. Appropriate fractions were combined and evaporated to give the title compound (2.10 g), m.p. 96°-98°.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].C(N(S(F)(F)[F:62])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([F:62])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
Treatment of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile as in Example 64 yields 17-ethyl-1-hydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:19]Br>C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([Br:19])([C:10](=[O:18])[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(Br)(C(=O)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of 36 g (0.145 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 175 ml of chloroform was treated with fifteen ml of bromine. The mixture was heated at reflux for one hour and then allowed to stand overnight at room temperature. 1-Acetyl-4-bromo-4-(p-fluorobenzoyl)piperidine precipitated and was collected by filtration and recrystallized from ethanol. Yield 40.6 g, melting point 156°-159° C. In the same manner, additional intermediates of this type are produced by substituting the selected starting materials from Preparation 2 or 11 in the procedure of Preparation 4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COCCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield an off-white solid (51%). LCMS: m/z=581.26 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, 1H, J=8.8, 1.3 Hz), 8.04 (d, 1H, J=1.5 Hz), 7.78 (m, 1H), 7.60 (d, 2H, J=6.6 Hz), 7.38 (m, 1H), 7.27 (m, 1H), 6.53 (m, 1H), 6.42 (m, 1H), 3.89 (m, 8H), 3.88 (m, 3H), 3.28 (d, 3H, J=1.8 Hz), 2.17 (m, 4H), 1.32 (m, 6H).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH3:17])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C(N([CH2:34][C:35]([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+]>Cl[Ni]Cl.C1COCC1>[CH3:6][C:7]([C:34]#[C:35]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=12)[CH3:17])([CH3:16])[CH3:8]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Reactant: CN(C/C=C/Cl)Cc1cccc2ccccc12
Agent: Cl[Ni]Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2ccccc12
Temperature: 50 °C

Procedure:
The mixture is cooled to 50° C. and 15.5 g (0.0572 mol) crude N-(trans-3-chloro-2-propenyl)-N-methyl-1-naphthalene-methylamine, 20 ml THF and 74 mg NiCl2 (0.77 molar percent) introduced. The reaction mixture is heated at 90°-95° C. for 1 hour, cooled to 20°/25° C. and 130 ml of a 2.5% (w/v) aqueous solution of EDTA disodium salt added, the phases are separated and the aqueous phase re-extracted with 70 ml chilled toluene. The combined organic phases are washed with 2×90 ml water and concentrated to a residue, thus giving 18.2 g (greater than theoretical yield) terbinafine with a purity of 83.6% (HPLC A %).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ncc2ccc(=O)n(C3CCCC3)c2n1
Reactant: Nc1ccccn1
Product: O=c1ccc2cnc(Nc3ccccn3)nc2n1C1CCCC1
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 7 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.7 mmol) prepared as in Example 107 of WO 98/33798 (incorporated herein by reference) and 2-aminopyridine (130 mg, 1.4 mmol) were combined in a 10 mL round-bottomed flask. The flask was purged with nitrogen (10 min), then heated in a 160° C. oil bath (30 min). After cooling, the orange residue was triturated with water to afford an orange solid, which was further purified by reversed-phase HPLC purification. [Vydac C18 TP254 (30 mm×100 mm); A: ACN (acetonitrile)+0.1% TFA (trifluor acetic acid); B; H2O+0.1% TFA; 10%-76% B over 40 min]. 15 mg of 8-cyclopentyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one was isolated as a yellow solid. Mp: >250° C., Anal. HPLC [Vydac C18 TP254 (4.6×150 mm); A: ACN+0.1% TFA; B; H2O+0.1% TFA; 10%-76% B over 20 min]: >98% Rt=13.9 min.