Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([CH3:11])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([CH3:11])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)nc1C#N
Solvent: ClCCl
Product: Cc1ccc(CCl)nc1C#N
Yield: 96 %

Procedure:
A solution of 6-(Hydroxymethyl)-3-methyl-2-pyridinecarbonitrile (148 mg) and thionyl chloride (0.16 ml) in dichloromethane (3.5 ml) was stirred at ambient temperature for 6 hours. Solvent was removed in vacuo and toluene (2 ml) added then removed in vacuo to afford the title compound (160 mg, 96%) as a pale grey-green solid.
Reaction SMILES: [H-].[Al+3].[H-].[H-].[Cl:5][C:6]1[CH:28]=[CH:27][C:9]2[C:10]3[N:25]([CH3:26])[N:24]=[CH:23][C:11]=3[C:12](=[O:22])[O:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:8]=2[CH:7]=1>O1CCCC1>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]2[N:25]([CH3:26])[N:24]=[CH:23][C:11]=2[CH2:12][OH:22])=[C:8]([CH:14]([OH:13])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:7]=1
Reactant: Cn1ncc2c1-c1ccc(Cl)cc1C(c1ccccc1F)OC2=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1ncc(CO)c1-c1ccc(Cl)cc1C(O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of approximately 33 m moles of aluminum hydride in 50 ml of tetrahydrofuran is added a solution of 6.86 g of 8-chloro-6-(2-fluoro-phenyl)-1-methyl-4-oxo-1H,6H-pyrazolo[4,3-d](2)benzoxepine in 150 ml of dry tetrahydrofuran under an atmosphere of nitrogen. After the addition, the mixture is stirred an additional 30 minutes in an ice bath. The excess of the reagent is then carefully destroyed by adding water; 50 ml of 2N hydrochloric acid is added to dissolve the voluminous precipitate. The two layers are separated, the organic layer is washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. All aqueous layers are reextracted with diethyl ether. The residue (consisting of a mixture of thermally interconvertible isomers) is taken up in 100 ml of dioxane and refluxed for 2 hours. The dioxane is then removed under reduced pressure and the residue is crystallized from 30 ml of diethyl ether to give the thermodynamically more stable isomer of the 3-[4-chloro-2-(2-fluoro-α-hydroxy-benzyl)-phenyl]-4-hydroxymethyl-2-methyl-pyrazole, m.p. 152°-155°. The mother liquor is equilibriated again by refluxing in dioxane and an additional amount of the product, m.p. 153°-155°, can be collected.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:17](/[C:16](/[F:15])=[CH:20]\[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C(F)=Cc1ccccc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C(F)=C\c3ccccc3)nc2n(CC)c1=O
Yield: 57.9 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 1.08 g (5.47 mmol) of 5,6-diamino-1,3-diethyluracil and 1.00 g (6.02 mmol) of α-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.04 g (yield 58%) of Compound 137 as white plates.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9]O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[C:25]([OH:28])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:9][CH2:10][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: c1ccc(C2CCOC2(c2ccccc2)c2ccccc2)cc1
Agent: Br
Product: CC(=O)OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
30.0 g of 2,2,3-triphenyltetrahydrofuran are dissolved in 125 ml of acetic acid, after which 25 ml of 40% hydrogen-bromide in acetic acid are added. The mixture is stirred for 1 h at 75° C. The solvent is evaporated, and 1M sodium carbonate solution is added in excess. The product is extracted in toluene. The toluene solution is dried over sodium sulfate and the solvent is evaporated. The product is recrystallized from aqueous methanol and then has m.p. 81°-3° C. The yield is 28.7 g (84%).
Reaction SMILES: [C:1]([CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([OH:29])[C:20]2[N:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:23][CH:24]=2)[CH3:16])=[CH:10][CH:9]=1)[CH3:7])([O:3][CH3:4])=[O:2].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=O>>[C:1]([CH:5]=[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([N:17]2[CH2:18][CH:19]([C:20]3[N:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[S:23][CH:24]=3)[O:29][CH:31]2[C:30]([O:34][CH3:35])=[O:33])[CH3:16])=[CH:12][CH:13]=1)[CH3:7])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CC(C)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: COC(=O)C=O
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC2C(=O)OC)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-(2-carbomethoxy-1-methylethyl)phenyl)-1-methyl-ethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with methyl glyoxylate followed by purification of the base on a silica gel column using chloroform/petroleum ether/ethyl acetate =5:4.5:0.5 as eluant.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+].CCOCC>C(O)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]5[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc(N)c3)n2)cc1
Temperature: 75 °C

Procedure:
To a solution of N-cyclopentyl-2-(4-methoxyphenyl)-3-[2-(3-nitroanilino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (167 mg, 0.32 mmol) in ethanol (10 mL) was added tin(II)chloride dihydrate (304 mg, 1.60 mmol). The mixture was heated to 75° C. for 8 hours and then cooled to room temperature. Saturated aqueous sodium bicarbonate was added followed by ether. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by flash chromatography (1:1 hexanes-ethyl acetate to 100% ethyl acetate) to provide_N′-{4-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-1,3-benzenediamine (40 mg, 25%) as a yellow solid. 1H NMR (CDCl3): δ 8.15 (d, 1 H), 7.82 (d, 1H), 7.64 (d, 2 H), 7.43 (s, 1 H), 7.34 (t, 1 H), 7.15-7.10 (m, 2 H), 7.03 (d, 2 H), 6.86 (d, 1H), 6.55 (d, 1 H), 6.40 (d, 1 H), 6.11-6.06 (m, 2 H), 4.05 (m, 1 H), 3.91 (s, 3 H)<3.69 (broad, 2 H), 2.18 (m, 2 H), 1.90-1.66 (m, 6 H); MS m/z 492 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[OH:17])[C@@:9]3([O:24][CH3:25])[C@H:10]([CH3:23])[CH2:11][C:12](=[O:22])[CH2:13]4.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[O:17][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@:9]3([O:24][CH3:25])[C@H:10]([CH3:23])[CH2:11][C:12](=[O:22])[CH2:13]4
Reactant: Brc1ccccc1
Reactant: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2c(c1Oc1ccccc1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3

Procedure:
To a solution of 3,14-dimethoxy-[α,17-dimethyl-4-hydroxymorphinan-6-one (21) (0.4 g, 1.159 mmol) in dry pyridine (1 ml) was added bromobenzene (0.205 g, 1.35 mmol) and 0.216 g (1.565 mmol) of K2CO3 (freshly dried at 110° C. for 2 hours in a vacuum oven and quickly ground and sieved to 200 mesh). More pyridine (0.5 ml) followed by copper powder (20 mg, 10 micron) was added and the mixture was refluxed (oil bath temperature 130°-140°) for 24 hours under a nitrogen atmosphere with stirring. The mixture was filtered while hot and the residue was washed with hot pyridine (2 ml). After adding 10 ml of toluene, the solution was concentrated under reduced pressure to give (22) as a foamy solid. Thin layer chromatography on a silica gel plate (solvent system: CHCl3 :MeOH, 80:20) showed a single spot. The compound was quickly chromatographed on a silica gel column and eluted with graded methanol/chloroform mixtures to give 0.45 g (92% theory) of 3,14-dimethoxy-8α,17-dimethyl-4-phenoxymorphinan-6-one (22) as a foamy solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][C:6]([CH2:13]Br)=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1([C:25]2[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.[NH4+].[Cl-]>[CH3:15][O:16][C:17]([C:19]1([C:25]2[CH:26]=[C:27]([F:32])[CH:28]=[C:29]([O:31][CH2:13][C:6]3[CH:5]=[C:4]4[C:9]([C:10]([Br:12])=[CH:11][C:2]([Br:1])=[N:3]4)=[CH:8][CH:7]=3)[CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: BrCc1ccc2c(Br)cc(Br)nc2c1
Reactant: COC(=O)C1(c2cc(O)cc(F)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Br)cc(Br)nc4c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dibromo-7-bromomethyl-quinoline (1.0 g, 2.6 mmol), 4-(3-fluoro-5-hydroxy-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (1a, 670 mg, 2.6 mmol), and cesium carbonate (1.7 g, 5.3 mmol) were suspended in DMF (15 mL) and stirred overnight at room temperature. The mixture was diluted with EtOAc and saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the desired product, 1b.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:12][OH:13]>>[CH3:12][O:13][C:7]([C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[C:10]([OH:9])=[O:11])=[O:8]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: CO
Product: COC(=O)[C@H]1CCCC[C@H]1C(=O)O
Yield: 100 %

Procedure:
A mixture of 2 g (0.013 mol) of cis-1,2-cyclohexane-dicarboxylic anhydride in 15 mL of methanol was refluxed for 5 hr, then evaporated to dryness under reduced pressure to give 2.41 g (100% yield) of cis-2-methoxycarbonyl-cyclohexanecarboxylic acid. When this was substituted for 3 in Example 1, the identical process afforded the title compound, melting at 140°-144° C., in 36% yield; Rf (D)=0.53, 0.47.
Reaction SMILES: CN(C)C=O.[O:6]([CH2:13][CH2:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:24][CH2:25][CH:26]([C:28]1[CH:33]=[C:32]([Cl:34])[C:31]([NH2:35])=[C:30]([Cl:36])[CH:29]=1)[OH:27]>C(OCC)(=O)C.CO.C(N(CC)CC)C>[O:6]([CH2:13][CH2:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:24][CH2:25][CH:26]([C:28]1[CH:29]=[C:30]([Cl:36])[C:31]([NH2:35])=[C:32]([Cl:34])[CH:33]=1)[OH:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCCBr)OCCOc1ccccc1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(C(O)CNCCCCCC(=O)OCCOc2ccccc2)cc1Cl

Procedure:
According to method I (dimethylformamide, 1 hour at 100° C.) from (2-phenoxyethyl)6-bromohexanoate and 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol. Working up by means of chromatography (ethyl acetate/methanol/triethylamine 16:2:1). Recrystallized as the base from diethyl ether. Melting point: 46°-47° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:24]4[CH2:29][CH2:28][S:27][CH2:26][CH2:25]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: C1CSCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: c1cc(C2(CN3CCSCC3)CCOCC2)ccc1OCCCN1CCCC1
Yield: 55.4 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (1.5 g, 4.726 mmol, 1 wt), thiomorpholine (930 mg, 9.027 mmol), absolute ethanol (60 ml), activated 3 Å molecular sieves (1.5 g), titanium (IV) isopropoxide (6.97 ml, 23.630 mmol) and STAB (8.51 g, 40.15 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by column chromatography on silica eluting with DCM(95):MeOH(4):NH3(I) to give the title compound as a pale yellow oil (1.06 g, 55%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.75 (dt, 2H), 3.57-3.45 (m, 2H), 2.63 (t, 2H), 2.59-2.39 (m, 12H), 2.36 (s, 2H), 2.14-1.95 (m, 4H), 1.92-1.73 (m, 6H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][C:6]1([CH3:16])[O:11][CH2:10][C:9]([CH2:14][CH3:15])([CH:12]=[O:13])[CH2:8][O:7]1.[Cl-].[NH4+]>O1CCCC1>[CH3:5][C:6]1([CH3:16])[O:7][CH2:8][C:9]([CH2:14][CH3:15])([CH:12]([OH:13])[CH2:1][CH3:2])[CH2:10][O:11]1
Reactant: CCC1(C=O)COC(C)(C)OC1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)C1(CC)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl magnesium bromide (70 ml, 1.3M in tetrahydrofuran) was stirred at 0°, under nitrogen. 2,2-Dimethyl-5-ethyl-5-formyl-1,3-dioxane (10.3 g.) in dry tetrahydrofuran (20 ml.) was added and the mixture was stirred at room temperature for three hours. The mixture was then refluxed, with stirring, for one hour. Saturated aqueous ammonium chloride solution was added to the cooled reaction mixture. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel, eluting with 40% ether hexane. 2,2-Dimethyl-5-ethyl-5-(1-hydroxy propyl)-1,3-dioxane was obtained as a colourless oil (10.0 g.).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:11]([C:7]2[N:8]=[CH:9][CH:10]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:6]=23)[C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:31])=[CH:28][CH:27]=1
Reactant: Cn1ccc2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c21
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ccc2ccnc(N(C(=O)c3ccc(Br)cc3)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a solution of Preparation 4 (R)-tert-butyl 3-((1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)amino)piperidine-1-carboxylate (45.0 g, 136 mmol) and 4-bromobenzoyl chloride (31.3 g, 143 mmol) in dry THF (250 mL) was added 1 M lithium bis(trimethylsilyl)amide (163 mL, 163 mmol) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 15 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by recrystallization (petroleum ether:EtOAc=2:1) to afford the title compound as an off-white solid (50 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:16][CH:13]([CH3:15])[CH3:14])=[N:7][N:6]=[CH:5]2
Reactant: CC(C)N
Reactant: Clc1nncc2cc(Br)ccc12
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nncc2cc(Br)ccc12
Temperature: 125 °C

Procedure:
In a sealed glass tube, a mixture of 6-bromo-1-chlorophthalazine (18, 0.40 g, 1.64 mmol), isopropyl amine (0.420 mL, 4.92 mmol) in NMP (2.0 mL) was heated in a microwave at 125° C. for 15 minutes. The resulting brown mixture was loaded on a 40 g ISCO column (eluted with 35-100% EtOAc in Hexanes) and purified to provide the title compound a light yellow crystalline solid. MS (ESI, pos. ion) m/z: 266.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[C:33]([O:34][CH3:35])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cnc1OC
Yield: 54.3 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (63 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (51 mg, 55%). ESI-MS m/z calc. 469.44. found 470.5 (M+1)+. Retention time 2.03 minutes.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.[C:18]1([Si:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)Cl)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C1COCC1.CC(O)C>[C:32]1([Si:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:1][N:2]=[C:3]2[CH:8]=[CH:7][C:6](=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10]#[N:11])[CH:5]=[CH:4]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC(=C1C=CC(=NO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)C=C1)c1ccccc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
7 g (31 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile, prepared as described in example 1.1, are dissolved in 80 ml of THF and cooled in an ice bath. After adding 10 g (34 mmol) of triphenylchlorosilane to the solution, 4.7 g (47 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. While the reaction mixture is stirred at 5° C. for 90 min, a precipitate is formed. The precipitate is filtered off and washed with THF. The filtrate is concentrated by a rotary evaporator to afford a red liquid. The residue is diluted with 2-PrOH and stirred at room temperature for 30 min. After cooling the mixture in an ice bath, the solid is isolated by filtration and washed with 2-PrOH. The product is obtained in the form of a pale yellow solid, mp 161-165° C. (Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 6.79(Z)/6.94(E) (dd, 1H), 7.04(Z)/7.15(E) (dd, 1H), 7.32-7.71 (m, 22H). 1H-NMR reveals that the product is a 77:23 mixture of Z and E isomers. The signals are tentatively assigned to Z and E isomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:9]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[CH3:10].[K+].[Br-]>>[CH2:9]([C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[NH:2])=[CH:13][CH:12]=1)[CH3:10]
Reactant: N#Cc1cccnc1
Reactant: CCc1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Product: CCc1ccc(NC(=N)c2cccnc2)cc1
Yield: 84.9 %

Procedure:
The title compound was prepared from 3-cyanopyridine (8.5 g, 83 mmol) and 4-ethylaniline (10 g, 83 mmol) by following the procedure described in preparation 10 (15.8 g, yield 84.9%, mp 134-136 C, purity 99.8% by HPLC). 1H-NMR (CDCl3):δ 1.22-1.26 (t, 3H), 2.60-2.65 (q, 2H), 5.09 (bs, 2H, D2O exchangeable), 6.88-6.89 (d, 2H), 7.18-7.19 (d, 2H), 7.32-7.35 (m, 1H), 8.18-8.20 (d, 1H), 8.64-8.65 (d, 1H), 9.03 (s, 1H). IR (KBr) cm−1: 3302, 3108, 2965, 2928, 2844, 1655. MS m/z: 227.1 (M+).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][NH:11][C:12]1[S:16][N:15]=[C:14]([CH3:17])[N:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:17][C:14]1[N:13]=[C:12]([N:11]([CH3:10])[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[S:16][N:15]=1
Reactant: CNc1nc(C)ns1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nsc(N(C)C(=O)C2CCCCC2)n1

Procedure:
Cyclohexane carboxylic acid chloride (9.92 g, 0.068 mol) was added slowly to a solution of 5-methylamino-3-methyl-1,2,4-thiadiazole (7.0 g, 0.054 mol) in dry benzene containing triethylamine (6.87 g, 0.068 mol) and the mixture heated under reflux for 11/2 hours, cooled and washed with 2 N hydrochloric acid, saturated solution sodium hydrogen carbonate and water; dried over magnesium sulphate, filtered and evaporated down to yield yellow oil which crystallised upon standing. This was recrystallised twice from petroleum ether 60°-80° C. to yield off-white crystals of N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-methylcyclohexane carboxamide. Yield 8.23 g, (63.8%), m.p. 96° C.
Reaction SMILES: [CH:1]1[C:22]2[C:21](=O)[C:20]3[C:7](=[CH:8][C:9]4[C:10](=O)[C:11]5[C:16]([C:17](=O)[C:18]=4[CH:19]=3)=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(CC)[O-].CC(CC)[O-].CC(CC)[O-].[Al+3]>C1(O)CCCCC1>[CH:4]1[C:5]2[C:22](=[CH:21][C:20]3[C:7]([CH:6]=2)=[CH:8][C:9]2[C:18](=[CH:17][C:16]4[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:19]=3)[CH:1]=[CH:2][CH:3]=1
Reactant: O=c1c2ccccc2c(=O)c2cc3c(=O)c4ccccc4c(=O)c3cc12
Agent: CCC(C)[O-]
Agent: [Al+3]
Solvent: OC1CCCCC1
Product: c1ccc2cc3cc4cc5ccccc5cc4cc3cc2c1
Temperature: 145 °C

Procedure:
To a mixture of 1.0 gram of pentacene-5,7,12,14-tetrone in 100 mL of cyclohexanol was added 7.3 grams of aluminum tri(sec-butoxide). The reaction mixture was heated to 145° C. for 66 hours. The reaction mixture was cooled to room temperature and placed in a centrifuge. A dark solid was separated and washed 3 times with cyclohexanol followed by centrifugation. The residue was washed with acetone, isolated on a filter flask, and air dried to give pentacene