Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][C:24]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol) and 3-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.6 mg, 0.30 mmol) and piperidine (3 drops) in ethanol was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 124 mg (100%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.41 (s, 1H, NH), 11.77 (br s, 1H, NH), 9.22 (br s, 1H), 8.32 (s, 1H), 7.72 (dd, J=2.7 & 6.6 Hz, 1H), 7.42 (m, 1H), 7.32-7.37 (m, 2H), 6.58 (d, J=1.8 Hz, 1H), 3.68 (m, 4H, 2×CH2), 2.36 (m, 4H, 2×CH2), 2.22 (s, 3H, CH3), 2.20 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:12])([CH3:11])[CH2:4][C@H:5]([NH2:10])[CH2:6][N:7]([CH3:9])[CH3:8].C(N(CC)CC)C.[CH2:20]([O:22][C:23]([CH:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[N:26]1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=1)=[O:24])[CH3:21].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:20]([O:22][C:23]([CH:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[N:26]1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH:10][C@H:5]([CH2:6][N:7]([CH3:9])[CH3:8])[CH2:4][C:3]([CH3:12])([CH3:11])[CH3:2])[CH:34]=1)=[O:24])[CH3:21]
Reactant: CN(C)C[C@@H](N)CC(C)(C)C
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(C=O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(CN[C@H](CN(C)C)CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of (S)-4,4,N1,N1-tetramethyl-pentane-1,2-diamine hydrochloride salt (Intermediate 2, 0.921 g, 4.73 mmol) in methanol (10 mL) cooled in an ice bath (0° C.) was added triethylamine (2.19 mL, 15.7 mmol) and the solution was stirred at this temperature for 25 minutes. To this cooled solution was added 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (0.937 g, 3.15 mmol) in methanol (35 mL) after which the solution was allowed to warm to room temperature and stirred for 2 hours. The solution was cooled to 0° C. and sodium cyanoborohydride (0.461 g, 7.3 mmol) and acetic acid (4 mL) were added and the solution was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated under reduced pressure, partitioned between dichloromethane and saturated aqueous sodium bicarbonate and the layers were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude 2-{3-[((S)-1-Dimethylaminomethyl-3,3-dimethyl-butylamino)-methyl]-benzyl}1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester, which was carried on to the next step without further purification.
Reaction SMILES: C[O-].[Na+].C([O:7][C@H:8]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@@H:9]1[O:10][CH2:11][CH2:12][Br:13])(=O)C>CO>[O:10]([CH2:11][CH2:12][Br:13])[C@H:9]1[O:14][C@H:15]([CH2:26][OH:27])[C@@H:16]([OH:22])[C@H:17]([OH:18])[C@@H:8]1[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@H](OCCBr)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@H](OCCBr)[C@@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h

Procedure:
A solution of NaOMe (0.143 M, 0.7 mL) was added to a suspension of 4i (See FIG. 7) (1 g, 2.2 mmol) in MeOH (10 mL) under N2. After 3 hours, the resulting solution was passed through a Dowex 50W(H+) plug (2×1 cm, eluant MeOH) and the solvent removed. The residue was purified by flash chromatography (MeOH:EtOAc, 2:25) to give 2-bromoethyl α-D-mannopyranoside 4d (See FIG. 7) (The use of 4d as a reactant has been described previously, although no details of preparation or characterization were given. (U.S. Pat. No. 4,918,009 to Nilsson, which is hereby incorporated by reference)) (606 mg, 96%) as a white foam; [α]26D=+50.7 (c 0.91, H2O); IR (KBr) 3417 cm−1 (OH); 1H NMR (500 MHz, D2O, COSY) δ 3.38-3.44 (m, 3H, H-4, —CH2Br), 3.50-3.55 (m, 2H, H-5, H-6), 3.60 (dd, J2,3 3.5 Hz, J3,4 9.7 Hz, 1H, H-3), 3.66 (dd, J5,6′ 4.6 Hz, J6,6′ 11.2 Hz, 1H, H-6′), 3.68 (ddd, J4.6 Hz, J5.4 Hz ,J 11.7 Hz, 1H, —OCHH′—), 3.76 (dd, J1,2 1.8 Hz, J2,3 3.5 Hz, 1H, H-2), 3.81 (ddd, J5.1 Hz, J6.5 Hz, J11.7, 1H, —OCHH′—), 4.71 (d, J1,2 1.8 Hz, 1H, H-1); 13C NMR (100 MHz, D2O) δ 32.1 (—CH,Br), 61.7 (—OCH2—), 67.5, 68.4, 70.7, 71.3, 73.8 (C-2, C-3, C-4, C-5, C-6), 100.5 (C-1); HRMS m/z (FAB+): Found 308.9985 (M+Na+); C8H15O6 79BrNa requires 308.9950. NaSSO2CH3 (150 mg, 1.12 mmol) was added to a solution of 4d (See FIG. 7) (245 mg, 0.85 mmol) in DMF (10 mL) under N2 and warmed to 50° C. After 16 hours, the solution was cooled and the solvent removed. The residue was purified by flash chromatography (MeOH:EtOAc, 1:9) to give 1d (See FIG. 7) (217 mg, 80%) as a hygroscopic foam; [α]29D=+58.0 (c 1.34, H2O); IR (KBr) 3441 cm−1 (OH), 1314, 1132 cm−1 (S—SO2); 1H NMR (500 MHz, D2O) δ 3.31 (t, J 5.8 Hz, 2H, —CH2S—), 3.35 (s, 3H, CH3SO2—), 3.45 (t, J9.6 Hz, 1H, H-4), 3.49 (ddd, J4,5 9.8 Hz, J5,6 5.8 Hz, J5,6′ 1.9 Hz, 1H, H-5), 3.55 (dd, J5,6 5.8 Hz, J6,6′ 12.1 Hz, 1H, H-6), 3.60 (dd, J2,3 3.4 Hz, J3,4 9.0 Hz, 1H, H-3), 3.66 (dt, Jd 10.7 Hz, Jt 5.7 Hz, 1H, —OCHH′—), 3.69 (dd, J5,6′ 1.9 Hz, J6,6′ 12.1 Hz, 1H, H-6′), 3.77 (dd, J1,2 1.6 Hz, J2,3 3.4 Hz, 1H, H-2), 3.83 (dt, Jd 11.0 Hz, Jt 5.9 Hz, 1H, —OCHH′—), 4.72 (d, J1,2 1.6 Hz, 1H, H-1); 13C NMR (125 MHz, D2O) δ 36.7 (—CH2S—), 50.7 (CH3SO2—), 61.9 (—OCH2—), 66.7, 67.7, 70.9, 71.5, 74.0 (C-2, C-3, C-4, C-5, C-6), 100.8 (C-1); HRMS m/z (FAB+): Found 319.0528 (M+H+); C9H19O8S2 requires 319.0521.
Reaction SMILES: [CH:1]1([CH:4]2[CH:9]=[CH:8][C:7]3=[C:10]([CH:18]=O)[CH:11]=[C:12]([O:16][CH3:17])[C:13]([O:14][CH3:15])=[C:6]3[O:5]2)[CH2:3][CH2:2]1.[NH:20]([CH2:27][CH2:28][C:29]#[N:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[NH:20]([CH:27]=[C:28]([CH2:18][C:10]1[C:7]2[CH:8]=[CH:9][CH:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][C:6]=2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=1)[C:29]#[N:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C=O)c2c(c1OC)OC(C1CC1)C=C2
Reactant: N#CCCNc1ccccc1
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)c2c(c1OC)OC(C1CC1)C=C2
Temperature: 10 °C
Reaction time: 1 h

Procedure:
30 g of (RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde and 17.5 g of 3-anilinopropionitrile were dissolved in 300 ml of dimethyl sulphoxide under argon, cooled to 10° C. and treated portionwise with 13.5 g of potassium tert.butylate. Subsequently, the mixture was stirred at 10° C. for a further 1 hr. and at 20° C. for 5 hrs. For the working up, the mixture was poured on to 3 l of ice/water and extracted: 2×3 l of ethyl acetate, 2×3 l of water. The crude product was purified by silica gel chromatography with hexane/ethyl acetate 5:1 to 2:1 and crystallized from hexane/ethyl acetate. (RS)-3-Anilino-2-(2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl-methyl)acrylonitrile was obtained as white crystals, m.p. 140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:20]=[O:21]>C(#N)C>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:20]=[O:21]
Reactant: COc1ccc(O)cc1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(O)c(C=O)c1
Temperature: 45 °C
Yield: 74 %

Procedure:
A mixture of 600 g of acetonitrile, 186.2 g of 4-methoxyphenol (1.5 moles) and 214 g (2.25 moles) of anhydrous magnesium chloride was warmed to 45° C. and 227.4 g (2.25 moles) of triethylamine was added dropwise at that temperature. Paraformaldehyde (150 g, 4.75 moles) was then added and the reaction was heated to reflux. Methanol was removed over 3 hours by distillation, using a 10-inch column packed with Penn-State packing. The weight of the methanol removed (vapor temperature 60-65° C.) was 130 g. The solution was cooled to 60° C. and added to 900 mL of water. The solution was acidified with 240 mL of conc. HCl and extracted with 150 g of ethyl acetate. The ethyl acetate solution was washed once with 300 mL of tap water, clarified through diatomaceous earth, and stripped on a rotary evaporator at 10 mm pressure and 85° C. bath temperature. The weight of the product was 206.5 g, the liquid chromatograph area percent was 86%, and liquid chromatograph weight percent was 82%. The overall assay yield was 74%.
Reaction SMILES: COC1C=C(C=CC=1)CO.C[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:18](=[O:19])[O:17][CH2:16]2.COC1C=CC=C2C=1C(=O)OC2>>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:18](=[O:19])[O:17][CH2:16]2
Reactant: COc1ccc2c(c1)COC2=O
Agent: COc1cccc(CO)c1
Agent: COc1cccc2c1C(=O)OC2
Product: O=C1OCc2cc(O)ccc21

Procedure:
The reactions are also highly stereo- and regiospecific. Thus, thallation-carbonylation of cis- and trans-2-phenylcyclohexanoles (examples 7 and 8) provide exclusively the cis and trans fused tricyclic lactones respectively. Substituents on the aromatic ring are also observed to effect a very pronounced directive effect. For example, thallation-carbonylation of m-methoxybenzyl alcohol affords the 5-methoxyphthalide in 89% yield and only a trace of the 7-methoxyphthalide (example 4). Similarly, m-hydroxybenzyl alcohol affords a 95% isolated yield of pure 5-hydroxyphthalide (example 5).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[OH:22][CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][C:28](=[O:34])[NH:29]2>>[OH:22][CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[C:27](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:28](=[O:34])[NH:29]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(CCO)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 33.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (prepared according to US2004186160) as starting materials to give 2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.3%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:25])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[C:48]1([C:54]2[NH:58][N:57]=[C:56]([SH:59])[N:55]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[CH:2]([S:59][C:56]3[NH:55][C:54]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[N:58][N:57]=3)[C:7](=[O:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1n[nH]c(-c2ccccc2)n1
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Sc3nnc(-c4ccccc4)[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one Step 1 of example C(40), was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Phenyl-1H-1,2,4-triazole-3-thiol was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[C:9](OS(C(F)(F)F)(=O)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:25]([C:9]1[CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)#[N:26]
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc(-c2ccccc2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)nc(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Zinc cyanide (4 g) and Pd(PPh3)4 (1.16 g) were added to a DMF (60 mL) solution of methyl 2-phenyl-6-{[(trifluoromethyl)sulfonyl]oxy}pyridine-4-carboxylate (3.7 g), and stirred at 90° C. for 3 hours. The reaction liquid was filtered through Celite, the solvent was partly evaporated away, the residue was diluted with ethyl acetate, water was added to it, and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered and the solvent was evaporated away. The residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12](=[O:18])[NH:13][N:14]=[C:15]([Cl:17])[CH:16]=1)=O>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:11]1[C:12](=[O:18])[NH:13][N:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: Nc1ccccc1NC(=O)c1cc(Cl)n[nH]c1=O
Solvent: CC(=O)O
Product: O=c1[nH]nc(Cl)cc1-c1nc2ccccc2[nH]1

Procedure:
A solution of 26.4 g of 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (2-aminophenyl)amide in 500 ml of acetic acid is stirred at 110° C. for 2.5 hours and then the solvent is distilled off. The crude product obtained in this way is employed without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(Nc2ccccn2)c1
Yield: 64.8 %

Procedure:
A suspension of methyl 2-chloroisonicotinate (1.00 g, 5.83 mmol), 2-aminopyridine (658 mg, 6.99 mmol), tris(dibenzylideneacetone)dipalladium(0) (107 mg, 0.17 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (139 mg, 0.29 mmol) and tripotassium phosphate (3.09 g, 14.6 mmol) in toluene (30 mL) was heated under reflux under an argon atmosphere overnight. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=9/1-2/3) and recrystallized from hexane/ethyl acetate to give the title compound (866 mg, yield 65%) as colorless crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[N:16]=2)=[C:12]([O:24][CH3:25])[CH:11]=1>CN(C=O)C>[F:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]2[CH:22]=[CH:23][C:10]([CH2:9][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:11][C:12]=2[O:24][CH3:25])[N:16]=1
Reactant: c1c[nH]cn1
Reactant: COc1cc(CCl)ccc1Oc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cn2ccnc2)ccc1Oc1cccc(F)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of imidazole (18 mg; 0.27 mmol) and NaH (12 mg; 0.30 mmol) in DMF (1 mL), under argon, was added a solution of 2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoropyridine (65 mg; 0.24 mmol) in DMF (1 mL). The reaction mixture was allowed to stir overnight, to 40° C. After concentration, the reaction was hydrolysed with saturated NH4Cl (1 mL), extracted with AcOEt (2*1 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (68 mg; 93%) was obtained.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[OH:9][CH2:10][C:11]([CH3:15])([CH2:13]O)[CH3:12].S(=O)(=O)(O)O>ClCCl>[CH3:12][C:11]1([CH3:15])[CH2:10][O:9][C:4]2([CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]2)[O:7][CH2:13]1
Reactant: O=C1CCC(=O)CC1
Reactant: CC(C)(CO)CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(C)COC2(CCC(=O)CC2)OC1

Procedure:
1,4 cyclohexane dione (20.0 grams) and neopentyl glycol (18.6 grams) were dissolved in dichloromethane (160 ml). Then sulfuric acid (3.2 grams) was added to the reaction solution at an ambient temperature and stirred till the reaction substantially completes, accompanied by cooling the reaction mixture to 10–20° C. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution (80 ml) and separated the organic layer from the resulting biphasic mixture. The solvent was distilled off from organic layer till substantial completion under reduced pressure. Hexane (200 ml) was added to the resulting residual mass and followed by cooling the reaction mass to a temperature of 0–5° C. to filter the by-products. Then the solvent from the filtrate was distilled off till the substantial completion under vacuum to yield the desired 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=[O:16])[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2>CC(O)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=[O:16])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)O)c2ccccc2c1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c2c(c1OC)CCCC2
Reaction time: 14 h
Yield: 92.6 %

Procedure:
A mixture of 3,4-dimethoxy-1-naphthalenecarboxylic acid (2.34 g, 10.1 mmol) and 10% Pd/C (0.56 g) in HOAc (50 mL) was hydrogenated on Parr apparatus at 60° C. and 50 psi for 14 h. After filtration through diatomaceous earth, the solvent was removed in vacuo and water was added. The solid was collected by filtration and washed with water to yield the title compound as a yellow solid (2.21 g, 93%). 1H NMR (DMSO-d6) δ 12.69 (s, 1H), 7.30 (s, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 2.91 (s, 2H), 2.65 (s, 2H), 1.64 (m, 4H); MS m/z 235 (M−H).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:14](=O)[CH2:15][S:16][C:17]3[NH:22][CH2:21][CH2:20][CH2:19][N:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:14]3[N:22]4[CH2:21][CH2:20][CH2:19][N:18]=[C:17]4[S:16][CH:15]=3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(CSC1=NCCCN1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Br
Solvent: CC(=O)O
Product: Clc1ccc(C2(C3=CSC4=NCCCN34)CCC2)cc1Cl
Temperature: 25 °C

Procedure:
A suspension of 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3,4,5,6-tetrahydropyrimidin-2-ylthio)ethanone hydrobromide (2.0 g—prepared in a manner similar to that described above) in acetic acid (7 ml) was heated under reflux for 16 hours, then allowed to cool to ambient temperature. The solvent was removed in vacuo, the residue was triturated with ether (50 ml), and the resulting solid was collected by filtration, washed with ether (50 ml), and dried in vacuo at ambient temperature to give 3-[1-(3,4-dichlorophenyl)cyclobutyl]-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine hydrobromide as a white solid (1.7 g), m.p. 269° C.
Reaction SMILES: O[CH2:2][CH:3]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]=3[N:15]=[N:14]2)[O:4]1.C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1.[CH2:52]([O:54][P:55]([CH:60]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:59])[O:56][CH2:57][CH3:58])[CH3:53]>CS(C)=O.C(Cl)Cl>[CH2:52]([O:54][P:55]([CH:60]=[CH:2][CH:3]1[CH:7]2[CH:6]([O:10][C:9]([CH3:11])([CH3:12])[O:8]2)[CH:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]=3[N:15]=[N:14]2)[O:4]1)(=[O:59])[O:56][CH2:57][CH3:58])[CH3:53]
Reactant: CC1(C)OC2C(CO)OC(n3nnc4c(NC(=O)c5ccccc5)ncnc43)C2O1
Reactant: CCOP(=O)(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOP(=O)(C=CC1OC(n2nnc3c(NC(=O)c4ccccc4)ncnc32)C2OC(C)(C)OC12)OCC
Reaction time: 2 h
Yield: 29.6 %

Procedure:
Compound 6.3 (1.2 g, 2.91 mmol) was dissolved in 23 mL DMSO, and treated with DCC (3.6 g, 17.5 mmol) and DCA (0.24 mL, 2.91 mmol). The mixture was stirred for 2 h and then treated with 0.3 mL pyridine. Diethyl(triphenylphosphoranylidene)methylphosphonate (2.9 g, 6.98 mmol) was dissolved in 5 mL CH2Cl2 and it was added to the mixture dropwise and the mixture was stirred for 3 h. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with H2O three times, dried over MgSO4, filtered and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 100% EtOAc to 5% MeOH in EtOAc to give compound 6.4 (469 mg, 30% yield). 1HNMR (300 MHz, CD3OD) δ 1.17-1.35 (m, 6H), 1.46 (s, 3H), 1.64 (s, 3H), 3.85-3.97 (m, 4H), 4.04-4.12 (m, 1H), 5.01 (m, 1H), 5.33-5.45 (m, 2H), 5.81 (d, 1H, J=5.7), 6.63-6.77 (m. 1H), 7.57-8.12 (m, 5H), 8.87 (s, 1H). LRMS (ESI) MH+ C24H29N6O7P requires 545.2, Found 545.0.