Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][C:5]1=O)=O.C[OH:16]>Cl>[CH3:1][S:2][C:4]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH:5]=1
Reactant: CS(=O)C1Cc2ccccc2OC1=O
Reactant: CO
Agent: Cl
Product: CSc1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
A mixture of 3-(methylsulfinyl)chromanone (11 g), methanol (100 ml) and 1N hydrochloric acid (100 ml) is stirred at room temperature for 20 hrs. The methanol is removed at reduced pressure, and the aqueous residue is extracted with chloroform. The chloroform extracts are combined, extracted with 1N sodium hydroxide solution, washed with water, dried over MgSO4 and evaporated to give an oil. The oil is heated at 100° C. in 5N hydrochloric acid (100 ml) for 5 hrs. The solution is cooled, and the product which precipitated is filtered off. Recrystallization from methanol gives 3-(methylthio)chromone (2) as white crystals (7.2 g, 72%), mp 103°-105° C.
Reaction SMILES: [NH2:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH2:15](N(CC)CC)[CH3:16].C([Si](C)(C)C)#C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:9]([C:15]#[CH:16])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1cc(I)c(N)cc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: C1CCOC1
Product: C#Cc1cc(C#N)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (936 mg, 3.0 mmol), CuI (I) (57 mg, 0.3 mmol), PdCl2(PPh3)2 (105.3 mg, 0.15 mmol), triethylamine (1.01 g, 10 mmol) and ethynyl-trimethyl-silane (450 mg, 4.5 mmol) were mixed in THF (30 ml). The reaction mixture was stirred at room temperature overnight. Tetrabutylammonium fluoride (1.0 M in THF, 3.0 ml, 3.0 mmol) was added to the reaction mixture, which was then stirred at room temperature for 20 mins. The reaction mixture was quenched by addition of H2O and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated to yield crude product 4-amino-5-ethynyl-2-trifluoromethyl-benzonitrile.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1.[CH2:17](O)[CH2:18][OH:19].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:18]1[O:19][C:11]2([CH2:12][CH2:13][CH:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:16])[CH2:2][OH:1])[O:15][CH2:17]1
Reactant: O=C(CO)CCCCCCC1=CCCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CO)CCCCCCC1=CCCC12OCCO2

Procedure:
A solution of 5.5 g. of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-1-one (Example 88), 25 ml. of ethylene glycol, and 0.1 g. of P-toluenesulfonic acid in 200 ml. of toluene is reflucted for 40 minutes using a Dean-Stark trap. The solution is poured into saturated sodium bicarbonate. The mixture is extracted with benzene. The organic solution is washed three times with water and dried over magnesium sulfate. The solvent is removed to give 6.0 g. of the title compound.
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:17][NH2:18]>CCO>[NH2:6][C:5]1[NH:18][N:17]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: CSC(Nc1ccccc1)=C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1c(Nc2ccccc2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((methylthio)(phenylamino)methylene)malononitrile (3.2 g) in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(phenylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:24])[CH:16]([OH:23])[CH2:17][C:18]([O:20]CC)=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>O>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:24])[CH:16]([OH:23])[CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)C(C)c1cccc(C(=O)c2ccccc2)c1
Solvent: CCO
Solvent: O
Product: CC(c1cccc(C(=O)c2ccccc2)c1)C(O)CC(=O)O

Procedure:
A mixture of 818 mg of ethyl 4-(m-benzoyl-phenyl)-3-hydroxy-4-methyl-butyrate, 8 ml of ethanol, 0.8 ml of water and 0.2 ml of 14N potassium hydroxide was refluxed for 11/2 hours and then was evaporated to dryness under reduced pressure. The residue was taken up in 20 ml of water and the solution was acidified to a pH of 1 by progressive addition of a 1N hydrochloric acid solution and was then extracted with methylene chloride. The organic phase was washed with water and evaporated to dryness under reduced pressure to obtain 4-(m-benzoyl-phenyl)-3-hydroxy-4-methyl-butyric acid in the form of a product soluble in alcohols, methylene chloride and chloroform.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[CH:31]1([NH:34][C:3](=[O:2])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]3)=[N:6][CH:5]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NC1CC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 52 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (90 mg, 0.22 mmol), was converted, using cyclopropylamine instead of cyclopropanemethylamine, to the title compound (50 mg, 52%) which was obtained as a white solid. MS: m/e=440.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:3][CH2:2]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]([C:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=2)=[CH:9][NH:10]3)[CH2:2][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: c1cc(OCC2CC2)c2cc[nH]c2c1
Product: CN1CC=C(c2c[nH]c3cccc(OCC4CC4)c23)CC1

Procedure:
Beginning with 4.3 gm (22.9 mMol) 4-cyclopropylmethyloxy-1H-indole and 5.7 mL (45.9 mMol) 1-methyl-4-piperidone, 0.995 gm (33% based on recovered starting material) of the title compound were recovered as a light yellow solid.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=C\C(O)=O.[CH:9]([N:12]1[C:26]2[C:27]3[C:14]([CH2:15][C@@H:16]4[C@@H:21]([C:22]=3[CH:23]=[CH:24][CH:25]=2)[CH2:20][C@@H:19]([C:28]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:29])[CH2:18][NH:17]4)=[CH:13]1)([CH3:11])[CH3:10].Cl>C(OCC)(=O)C>[CH:9]([N:12]1[C:26]2[C:27]3[C:14]([CH2:15][C@@H:16]4[C@@H:21]([C:22]=3[CH:23]=[CH:24][CH:25]=2)[CH2:20][C@@H:19]([C:28]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:29])[CH2:18][N:17]4[CH2:1][CH3:2])=[CH:13]1)([CH3:11])[CH3:10]
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)OC3CCCCC3)CN[C@@H]1C2
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1C[C@H](C(=O)OC2CCCCC2)C[C@@H]2c3cccc4c3c(cn4C(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Two grams of 1-isopropyl-8β-cyclohexyloxycarbonylergoline maleate were converted to the free base by partitioning between 100 ml of (CH2Cl)2 and 100 ml. of saturated aqueous sodium bicarbonate. The free base passed into the organic layer. The organic layer was separated and the solvent evaporated therefrom. The resulting residue was dissolved in 15 ml of DMF, and 0.67 g of potassium carbonate and 0.75 g of ethyl iodide added to the solution. This reaction mixture was stirred at ambient temperature for about 3 days at which time HPLC indicated that starting material was no longer present. The reaction mixture was partitioned between 50 ml ethyl acetate and 50 ml of water. The organic layer was separated and the separated layer twice extracted with 50 ml portions of water. The organic layer was dried and the solvent removed by evaporation. The resulting residue (weight=1.67 g) comprising cyclohexyl 1-isopropyl-6-ethyl-8β-cyclohexyloxycarbonylergoline formed in the above reaction, was converted to the corresponding hydrochloride salt in ethyl acetate solution with gaseous HCl. Two crops of the crystalline salt were recovered by filtration; yield=1.42 g; purity by HPLC>99.2%. The crystalline fraction was slurried in a THF/ether solvent mixture and the slurry filtered. 1-Isopropyl-6-ethyl-8β-cyclohexyloxycarbonylergoline hydrochloride thus prepared melted above 220° C.; yield=1.33 g; molecular ion at 408.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][NH2:11].[C:12]([N:16]1[C:20](=[O:21])[C:19](Cl)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17]1(=[O:30])=[O:29])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:11][CH2:10][CH2:9][CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17]1(=[O:29])=[O:30])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCOc1ccccn1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccccn2)=C(c2ccccc2)S1(=O)=O
Yield: 65 %

Procedure:
The title compound was prepared as described for Example 24 from 1 equivalent of [3-(pyridin-2-yloxy)propyl]amine, 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1 equivalent TEA with a reaction time of 30 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using 5:1 petroleum ether 40-60° C. in EtOAc as eluent to give the title compound (0.178 g, 65%) as a solid. 1H NMR (500 MHz CDCl3): δ 8.17 (dd, 1H), 7.62-7.57 (m, 1H), 7.54-7.48 (m, 2H), 7.45-7.40 (m, 3H), 6.91-6.88 (m, 1H), 6.74 (d, 1H), 6.00 (t, 1H), 4.28 (t, 2H), 3.04 (q, 2H), 1.83 (quintet, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 163.8, 159.9, 147.0, 138.9, 135.5, 131.8, 129.7, 128.8, 125.4, 117.3, 111.5, 106.9, 63.6, 61.6, 42.0, 28.9, 27.9; Mass Spectrum: M+H+ 416.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=O)[N:10]=2)[N:7]=1.[CH3:16][NH2:17].O1CCCC1>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:17][CH3:16])=[O:13])[N:10]=2)[N:7]=1
Reactant: CN
Reactant: CCOC(=O)c1cn2nc(I)ccc2n1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.6 %

Procedure:
To a suspension of ethyl 6-iodoimidazo[1,2-b]pyridazine-2-carboxylate (4.5 g, 14.8 mmol) in methanol (13.5 mL) was added dropwise a solution of methylamine/tetrahydrofuran (2 mol/L, 37.1 mL, 74.2 mmol), and the mixture was stirred at room temperature for 96 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, saturated brine and water to give the title compound (3.2 g, 71%) as a dark brown powder.
Reaction SMILES: [C:1]([O-])(=[O:3])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[OH:18][C:19]1[C:39]([CH2:40][CH2:41][CH3:42])=[CH:38][C:22]2[CH:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[CH2:24][O:25][C:21]=2[CH:20]=1>CO>[CH3:1][O:3][C:22]12[CH:38]=[C:39]([CH2:40][CH2:41][CH3:42])[C:19](=[O:18])[CH:20]=[C:21]1[O:25][CH2:24][CH:23]2[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: CCCc1cc2c(cc1O)OCC2c1cc(OC)c(OC)c(OC)c1
Reactant: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CO
Product: CCCC1=CC2(OC)C(=CC1=O)OCC2c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lead tetraacetate (200 mg) was added to a solution of 6-hydroxy-3-(3,4,5-trimethoxyphenyl)-5-propyl-2,3-dihydrobenzofuran (100 mg) in dry methanol (10 ml), and the mixture was stirred at room temperature for 1 hour. The solution was evaporated to a residue, which was put on a flash column of silica gel and eluted with hexane-ethyl acetate (4:1, v/v). The title compound was isolated as a mixture of epimers.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH3:9]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of sodium hydride (3.22 g, 0.134 mole) in N,N-dimethylformamide (DMF)(150 mL) was added tert-butyl ethyl malonate (22.9 g, 0.122 mole). The resulting mixture was stirred at room temperature for 1 hour and then a solution of (2-bromoethoxymethyl)benzene (28.8 g, 0.134 mole) in DMF (150 mL) was added dropwise. After stirring at room temperature overnight, the mixture was poured into water (1000 mL) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and concentrated to an oil which was chromatographed on silica gel eluting with hexane and then 5% ethyl acetate in hexane to afford 2-(2-benzyloxyethyl)malonic acid tert-butyl ester ethyl ester as an oil (31.4 g, 80% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(Cl)Cl>[C:29]([Si:26]([CH3:28])([CH3:27])[O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(CCc1ccccc1)c1ccc(OCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)CCc2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 5 using 1-[4-(2-hydroxy-ethoxy)-phenyl]-3-phenyl-propan-1-one from Example N (2.21 g, 8.2 mmol), imidazole (0.67 g, 9.8 mmol), t-butyldimethylsilyl chloride (1.36 g, 9.0 mmol) and CH2Cl2 (70 mL). The product was carried on crude to the next step (see Example SS.)
Reaction SMILES: C([NH:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=2)=[CH:12][CH:11]=1)(=O)C.Cl>>[NH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)NCCNC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: Cl
Product: NCCNC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
5-[4-(3-(2-Acetamidoethyl)ureido)phenyl]-2(1H)-pyrazinone was hydrolysed by heating with hydrochloric acid to form the title compound, as the hydrochloride; δ(D2O/DCl) 3.15, 3.45 (2t, 4H, --CH2CH2 --), 7.81, 8.08 (2d, pyrazinone H's).
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C12(NC3C(C(N)=O)=CN=C(S(C)(=O)=O)N=3)CC(C1)C2.Cl.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:45][CH:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: NC1CCOCC1
Reactant: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Agent: CS(=O)(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(NC2CCOCC2)nc1NC12CC(C1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfinyl)pyrimidine-5-carboxamide, 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (300 mg) and tetrahydro-2H-pyran-4-amine hydrochloride (181.5 mg, 1.32 mmol) in NMP (10 mL) was added DIEA (426 mg, 3.3 mmol). The resulting mixture was stirred at 100° C. overnight. Then the reaction mixture was purified by preparative HPLC to give the desired product (221.3 mg, 0.73 mmol, yield 67%) as a yellow powder. 1H NMR (400 MHz, CD3OD) δ ppm 8.19 (s, 1H), 3.95-3.88 (m, 3H), 3.44-3.38 (m, 2H), 2.40 (s, 2.09 (s, 6H), 1.88-1.85 (m, 2H), 1.55-1.45 (m, 2H; MS (ESI) m/z=304.2 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[C:7]3[C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:5]=2[C:4]([CH3:19])=[C:3]1[Si:20]([CH3:23])([CH3:22])Cl)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[CH3:1][CH:2]1[C:6]2[C:7]3[C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:5]=2[C:4]([CH3:19])=[C:3]1[Si:20]([CH3:23])([CH3:22])[NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CC1=C([Si](C)(C)Cl)C(C)c2c1c1ccccc1c1ccccc21
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC1=C([Si](C)(C)NC(C)(C)C)C(C)c2c1c1ccccc1c1ccccc21

Procedure:
To a 500 ml round bottom flask containing 2.420 g (0.00718 mole) of (1,3-dimethyl-1H-cyclopenta[l]phenanthrene-2-yl)dimethylchlorosilane and 250 ml of methylene chloride was added 1.331 g (0.0180 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (Celite™), washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 2.120 g (79.0 percent). 1H NMR analysis indicated the predominant isomer was substituted at the 2 position.
Reaction SMILES: F[C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].O.Cl.O1CCC[CH2:17]1>>[CH3:17][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([F:11])=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: Cc1c(F)c(F)c(F)c(F)c1CO
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A solution of methyl bromide (9.6 g) in dry tetrahydrofuran (25 cm3) was added dropwise in a stirred mixture of magnesium turnings (5.0 g), dry tetrahydrofuran (50 cm3) and a small crystal of iodine at the ambient temperature (ca. 22° C.). When the addition was complete the mixture was stirred for a further 1 hour at the ambient temperature and the solution of methyl magnesium bromide thus formed was then added dropwise to a stirred solution to pentafluorobenzyl alcohol (17.8 g) in tetrahydrofuran (50 cm3) whilst the temperature was maintained at 30° C. When the addition was complete the mixture was stirred for a further 2 hours at the ambient temperature and for 3 hours at the reflux temperature. Water at 0° C. was added to the mixture, which was then acidified with dilute hydrochloric acid and extracted with diethyl ether (2×80 cm3). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (4.6 g) was shown by gas liquid chromatographic examination of a sample to consist of ca. 70% by weight of unreacted starting material and ca. 30% by weight of product. The oil was subjected to vigorous purification by column and thin-layer chromatography using a silica gel support and eluting with a mixture of diethyl ether and hexane (3:7 by volume), to obtain 2-methyl-3,4,5,6-tetrafluorobenzyl alcohol as a colourless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[NH:7][C:6]1=[O:16])[C:2]#[C:3][CH3:4].CI.[C:19](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]([CH3:19])[C:6]1=[O:16])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(=O)[nH]c2nc(Cl)nc(Cl)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(=O)n(C)c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
7-(2-Butynyl)-2,6-dichloro-7,9-dihydropurin-8-one (435 mg) was dissolved in N,N-dimethylformamide (10 mL), and then methyl iodide (158 μL) and anhydrous potassium carbonate (468 mg) were added to the solution. This reaction solution was stirred at room temperature for 12 hours, and then water (50 mL) was added. After stirring at room temperature for one hour, a white precipitate was collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (355 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([I:9])=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.BrC1C=C(C[N:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[CH:31]=[CH2:32])[C:21](=[O:23])[CH3:22])C(Cl)=NC=1.ClC1C(CN(C2C=CC=CC=2C=C)C(=O)C)=CC(F)=C(Cl)N=1>>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:2][N:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[CH:31]=[CH2:32])[C:21](=[O:23])[CH3:22])[C:8]([I:9])=[CH:7][N:6]=1
Reactant: C=Cc1cc(Cl)ccc1N(Cc1cc(Br)cnc1Cl)C(C)=O
Reactant: Clc1cc(CBr)c(I)cn1
Agent: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Product: C=Cc1cc(Cl)ccc1N(Cc1cc(Cl)ncc1I)C(C)=O

Procedure:
Compound 77B was prepared from 77A (0.75 mg, 0.22 mmol) and 76C (0.44 g, 0.22 mmol) using a procedure similar to the synthesis of 1C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]#[N:17])=[CH:8][CH:7]=1>ClCCl.C([O-])(O)=O.[Na+]>[N:5]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]#[N:17])=[CH:8][CH:7]=1)=[C:1]=[S:2]
Reactant: N#Cc1ccc(N)c2ccccc12
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(N=C=S)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
Thiophosgene (9.1 mL, 118.9 mmol) was added to a stirring slurry of 4-amino-1-naphthalenecarbonitrile (10 g, 59.45 mmol) in dichloromethane (200mL) and saturated aqueous NaHCO3 solution (200 mL) at 0° C., and the mixture stirred for 3 days at room temp. The layers were separated and the organic layer concentrated to provide 4-isothiocyanato-1-naphthonitrile as a tan solid (11.64 g, 93%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:22]1[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([C:7](=[N:8][CH:9]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Cn1cc(Br)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cnn(C)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
To a solution of 2.54 g of ethyl N-(diphenylmethylene)glycinate in 15 ml of toluene were added 1.52 g of 4-bromo-1-methyl-1H-pyrazole, 522 mg of bis(tri-tert-butylphosphine)palladium(0), and 6 g of tripotassium phosphate, followed by stirring at 100° C. for 12 hours. The reaction mixture was left to be cooled to room temperature and then filtered over Celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 328 mg of ethyl [(diphenylmethylene)amino](1-methyl-1H-pyrazol-4-yl)acetate.