Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]3[CH2:15][O:14][C:13](=[O:16])[C:9]3=[CH:10][CH:11]=2)[CH2:6][CH2:5][O:4]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[O:16]=[C:13]1[C:9]2[C:8](=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:3]([CH2:2][O:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[O:4][CH2:5][CH2:6]3)[CH2:15][O:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1OCc2c1ccc1c2CCOC1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2OCCc3c2ccc2c3COC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-(Hydroxymethyl)-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one, in DCM (10 mL) was treated with p-Toluenesulfonyl chloride (0.40 g, 2.3 mmol); to the mixture was added pyridine (2 mL) and the resulting mixture stirred at room temperature for 12 h. TLC (hexanes/EtOAc=1/0.5) and LC indicated the consumption of starting material and formation of the desired product. Reaction mixture was treated with dichloromethane and washed with NaCl, water and dried over Na2SO4, filtered and concentrated to dryness, absorbed into silica gel and was then subjected for purification over silica gel; (3-oxo-3,6,8,9-tetrahydro-1H-furo[3,4-f]isochromen-6-yl)methyl-4-methylbenzenesulfonate was isolated with the solvent system of hexanes/EtOAc (1/0.5). 1H-NMR (400 MHz, CDCl3) δ ppm 7.781 (d, J=8 Hz, 1H), 7.727 (d, J=8 Hz, 1H), 7.367 (d, J=8 Hz, 1H), 7.257 (d, J=8.5 Hz, 1H), 7.206 (d, J=8 Hz, 1H), 5.253 (s, 2H), 5.110 (s, 1H), 4.481-4.452 (in, 2H), 4.419-4.385 (m, 2H), 4.196-4.153 (m, 2H), 2.495 (s, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[Cl:18][C:19]1[N:28]=[C:27](Cl)[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1>CN(C)C=O>[ClH:18].[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:27]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=[C:19]([Cl:18])[N:28]=1
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cl
Product: Clc1nc2c(c(N3CCc4ccccc4C3)n1)CCCC2
Yield: 139.8 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that a mixture solution of 1,2,3,4-tetrahydroisoquinoline(2.8 ml, 22 mmol), triethylamine(3.4 ml, 24 mmol), N,N-dimethylformamide(10 ml) and 2,4-dichloro-5,6,7,8-tetrahydroquinazoline(4.0 g, 20 mmol) prepared in Step 2 of Example 32 were used as starting materials, 4.7 g of the titled compound was prepared. (Yield: 78.4%)
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#N.[OH2:16].[CH2:17]([OH:19])[CH3:18].[OH-].[Na+]>C(Cl)Cl>[CH3:15][N:12]1[CH2:11][CH2:10][N:9]([C:6]2[N:5]=[N:4][C:3]([C:1]([O:19][CH2:17][CH3:18])=[O:16])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: CN1CCN(c2ccc(C#N)nn2)CC1
Reactant: CCO
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCN(C)CC2)nn1
Temperature: 20 °C

Procedure:
Ethyl [6-(4-methylpiperazin-1-yl)pyridazin-3-yl]-carboxylate can be obtained by heating a suspension of 3-cyano-6-(4-methylpiperazin-1-yl)pyridazine (40.7 g ) in a mixture of distilled water (300 cc), ethanol (200 cc) and 10N aqueous sodium hydroxide (100 cc) at a temperature of about 80° C. for 5 hours. After cooling to a temperature of about 20° C., methylene chloride (200 cc) is added to the reaction mixture and the aqueous phase is decanted, acidified with 12N hydrochloric acid (100 cc) and evaporated to dryness under reduced pressure. Ethanol (250 cc), 1,2-dichloroethane (250 cc) and pure methanesulphonic acid (52.5 g) are added to the residue obtained. The resulting mixure is then heated under reflux for 20 hours. After cooling to a temperature of about 20° C., the insoluble material is filtered off and washed with methylene chloride (2 × 100 cc). A saturated aqueous solution of sodium carbonate (1000 cc) is added to the filtrate thus obtained. The resulting insoluble product is filtered off and washed with methylene chloride (2 × 200 cc). The aqueous phase is decanted and washed with methylene chloride (2 × 200 cc). The organic fractions are combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. Ethyl [6-(4-methylpiperazin-1-yl)pyridazin-3-yl]-carboxylate (9.5 g), melting at 106° C., is obtained. 3-Cyano-6-(4-methylpiperazin-1-yl)pyridazine can be prepared from 6-(4-methylpiperazin-1-yl)-3-iodopyridazine (125 g) and cuprous cyanide (55.26 g) suspended in dimethylformamide (620 cc). 3-Cyano-6-(4-methylpiperazin-1-yl)pyridazine (52.1 g), melting at 149° C., is obtained.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14](S([O-])(=O)=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4](S([O-])(=O)=O)=[CH:3][CH:2]=1.[K+].[K+].[OH-:23].[K+].[OH2:25]>>[C:4]1([OH:25])[CH:5]=[CH:6][C:1]([C:11]2[CH:16]=[CH:15][C:14]([OH:23])=[CH:13][CH:12]=2)=[CH:2][CH:3]=1
Reactant: O=S(=O)([O-])c1ccc(-c2ccc(S(=O)(=O)[O-])cc2)cc1
Reactant: O
Reactant: [OH-]
Agent: [K+]
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 310 °C
Yield: 95.6 %

Procedure:
Dipotassium 4,4'-biphenyldisulfonate (195 g) was added to 448 g of a 50% aqueous solution of potassium hydroxide, and the mixture was stirred. Then, 1680 g of a hydrogenated triphenyl mixture was mixed. The mixture was heated to 310° C. in an atmosphere of nitrogen, and with stirring, it was dehydrated. Thereafter, the mixture was stirred at 310° C. for 3 hours. After cooling, 1 liter of water was added to the reaction mixture to separate the triphenyl hydrogenated layer. The water layer was decolorized with activated carbon, and precipitated with dilute sulfuric acid to give 88.9 g (yield 95.6%) of 4,4'-biphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2cccc(F)c2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccc(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(3-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 4.96 (s, 2H), 6.48 (d, 1H), 7.10 (d, 1H), 7.19 (d, 1H), 7.31-7.50 (m, 11H), 7.94 (d, 1H), 7.98 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])C.C(Cl)(Cl)Cl>O1CCOC1>[C:1]([O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH2:11][C@@H:10]1[CH:29]1[O:32][CH2:33][CH2:34][O:31]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC[C@@H]1C=CC(=O)O1
Reactant: CCOC(C)=O
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1COCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Yield: 93 %

Procedure:
A solution containing 29.0 mg (0.146 mmol) compound (2d) and 3.0 mg (0.016 mmol) benzophenone in 20 mL [1,3]-dioxolane was irradiated at 0° C. for 1.5 hours according to the general procedure. Column chromatography (silica gel 15 g, ethyl acetate in hexanes 40%) gave compound (3d) (37 mg. 93%) as a colorless solid, Rf=0.21, [α]25D 23.8°, c 1.0, CHCl3, IR (neat) 1785, 1740, 1210, 740 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 1.21 (s, 9H), 2.57-2.60 (m, 1H), 2.67-2.75 (m, 2H), 3.91-3.93 (m, 2H), 4.01-4.04 (m, 2H), 4.37 (dd, 1H, J=4.2 Hz, J=12.2 Hz), 4.38 (dd, 1H, J=2.9 Hz, J=12.2 Hz), 4.69 (mc, 1H), 4.92 (d, 1H, J=3.6 Hz). 13C-NMR (100.6 MHz, CDCl3, Dept) δ: 27.14 (+), 29.75 (−), 38.70 (+) (quat), 65.26 (−), 65.43 (−), 65.58 (−), 77.37 (+), 103.30 (+), 175.47 (quat), 178.02 (quat). C13H20O6; Exact Mass: 272.13; Mol. Wt.: 272.29; C, 57.34, H, 7.40, O, 35.25.
Reaction SMILES: [C:1]([CH:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=O)[CH3:2].NC1NN=C(C2C=CC(OC3C=CC=CC=3)=CC=2)C=1C#N.NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C#N)=C3N=CC=2)C=CC=1.ClCCC(NC1C=C(C2[N:84]3[N:85]=[C:86]([C:91]4[CH:96]=[CH:95][C:94]([O:97][C:98]5[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=5)=[CH:93][CH:92]=4)[C:87]([C:88]([NH2:90])=[O:89])=[C:83]3[NH:82][CH2:81]C2)C=CC=1)=O>>[NH:6]1[CH2:5][CH:4]([CH:1]2[N:84]3[N:85]=[C:86]([C:91]4[CH:96]=[CH:95][C:94]([O:97][C:98]5[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=5)=[CH:93][CH:92]=4)[C:87]([C:88]([NH2:90])=[O:89])=[C:83]3[NH:82][CH2:81][CH2:2]2)[CH2:7]1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2C1CNC1

Procedure:
The desired product was prepared from tert-butyl 3-acetylazetidine-1-carboxylate and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to the procedures for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (step 4 to 5), compound 2 (step 1 and 2) and compound 38 (step 2), under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (DMSO-d6) δ 8.70 (br s, 1H), 8.44 (br s, 111), 7.50 (d, J=8.6 Hz, 2H), 7.45-7.40 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.4 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.72 (br s, 1H), 4.46-4.38 (m, 1H), 4.24-4.15 (m, 1H), 4.07-3.94 (m, 3H), 3.29-3.24 (m, 2H), 3.19-3.10 (m, 1H), 2.13-2.04 (m, 1H), 1.78-1.69 (m, 1H). MS (ESI) m/e [M+1]+ 390.0.
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1[C:22]2[C:17](=[N:18]C=[CH:20][CH:21]=2)[S:16][N+:15]=1[O-].C(NC(C)C)(C)C>ClCCl>[Cl:12][C:2]1[N:18]=[C:17]2[S:16][N:15]=[C:14]([CH3:13])[C:22]2=[CH:21][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c2cccnc2s[n+]1[O-]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cc1nsc2nc(Cl)ccc12
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of triphosgene (190 mmol) in dichloromethane (200 mL) was added dropwise over 20 min to a solution of 3-methylisothiazolo [5,4-b]pyridine-N-oxide (47.4 mmol) in dichloromethane (150 mL) at −20° C. A solution of diisopropylamine (190 mmol) in dichloromethane (200 mL) was added dropwise over 1 h. The reaction mixture was allowed to warm to rt and was maintained for 16 h. The reaction mixture was quenched with water (40 mL) of water and the pH was adjusted to 7 by the addition of 10% sodium hydroxide. The organic layer was washed with water (100 mL). The combined aqueous layers were extracted with dichloromethane (10×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (1/80 ethyl acetate/petroleum ether) to provide 6-chloro-3-methylisothiazolo[5,4-b]pyridine in 46% yield as a colorless solid.
Reaction SMILES: C([N:3](CC)CC)C.Cl.N=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[CH2:22]([N:24]=[C:25]=[S:26])[CH3:23]>CC(C)=O>[CH2:22]([NH:24][C:25]([CH:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:12][C:11]1=[NH:3])=[S:26])[CH3:23]
Reactant: CCN=C=S
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(C)=O
Product: CCNC(=S)C1C=CN(c2ccccc2)NC1=N
Yield: 8 %

Procedure:
5.3 g (52.4 millimoles) of triethylamine were added dropwise to 10.0 g (48.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 25 ml (24.9 g, 285 millimoles) of ethyl isothiocyanate at room temperature, while stirring. After the addition was complete, the reaction mixture was diluted with 50 ml of acetone, stirred for a further 2 hours at room temperature and then filtered. The residue was discarded. The filtrate was evaporated down, and the solid which remained was recrystallized first from isopropanol and then from ethyl acetate/hexane. 1.0 g (8% of theory) of 1,4-dihydro-4-(ethylthiocarbamyl)-imino-1-phenylpyridazine was isolated as yellow crystals of melting point 134°-135° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([C:25]([NH:27][CH:28]4[CH2:30][CH2:29]4)=[O:26])[CH:19]=3)=[CH:14][CH:13]=2)=[N:9][N:8]=1>O.CN(C=O)C.C(O)C>[N:1]([CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30]4)=[O:26])[CH:19]=3)=[CH:16][CH:17]=2)=[N:9][N:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1

Procedure:
A solution of sodium azide (14.8 mg) in water (1.25 ml) was added to 4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (40 mg) in DMF (0.5 ml) and ethanol (2.5 ml) and the mixture heated at reflux for 2 hours. The solvents were evaporated under vacuum and the residue partitioned between water (20 ml) and chloroform (15 ml). The aqueous was extracted with chloroform (15 ml) and the combined organic phases dried (sodium sulphate) and reduced to dryness in vacuo to give 4′-[5-(azidomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide,
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:13]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)[CH2:2]2
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: NC1CN2CCC1CC2
Product: COc1ccc(CCCC(=O)NC2CN3CCC2CC3)cc1
Yield: 28 %

Procedure:
Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine (200 mg, 1.00 mmol) and 4-(4-methoxy-phenyl)-butyric acid gave the title compound as a white solid (85 mg, 28%). 1H NMR (400 MHz, CD3OD) δ 7.08 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.18 (br s, 1H), 3.74 (s, 3H), 3.68 (d, J=11.6 Hz, 1H), 3.24-3.33 (m, 4H), 2.98-3.03 (m, 1H), 2.57 (t, J=7.6 Hz, 2H), 2.24 (t, J=7.6 Hz, 2H), 2.03-2.16 (m, 2H), 2.02 (br s, 2H), 1.85-1.91 (m, 3H) ppm. 13C NMR (400 MHz, CD3OD) δ 175.2, 158.3, 133.6, 129.2, 113.6, 54.5, 52.6, 47.2, 46.4, 44.5, 34.9, 34.2, 27.5, 24.4, 21.5, 17.1 ppm. Purity: 96.4% HPLCMS (210 nm); retention time 1.76 min; (M+1) 303.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:27][N:28]([CH3:33])[S:29](Cl)(=[O:31])=[O:30].O>CN(C=O)C>[CH3:24][C:19]1[C:18]([C:10]2[N:11]([S:29]([N:28]([CH3:33])[CH3:27])(=[O:31])=[O:30])[C:12]3[C:17]([C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: COc1ccc(-c2c(-c3c(C)noc3C)[nH]c3ccccc23)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(-c3c(C)noc3C)n(S(=O)(=O)N(C)C)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (the intermediate product of step (d) from Example 1, 35 mg, 0.11 mmol) was added to a suspension of NaH (25 mg, 60% in heptane) in DMF (dry, 0.7 ml) at 0° C. under nitrogen. The mixture was stirred at rt for 30 min and was then cooled to 0° C. again. Dimethylsulfamoyl chloride (2 eq) was added drop wise. The mixture was stirred at rt for 2 h, cooled to 0° C. and water was added to quench the reaction. Extraction with DCM using isolute phase separator and concentration of the combined organic layers afforded 2-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-N,N-dimethyl-1H-indole-1-sulfonamide in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24]CC2C=CC(OC)=CC=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:24])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: COc1ccc(COc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(Cl)cc(O)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Yield: 50 %

Procedure:
7-Chloro-5-(4-methoxy-benzyloxy)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (5.0 mg) was dissolved in a 1:1 mixture of trifluoroacetic acid and dichloromethane. The reaction was stirred over the weekend. The mixture was then washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound (1.87 mg). 1H NMR (300 MHz, CDCl3): δ 7.36 (d, 2H), 7.20 (d, 2H), 6.94 (s, 1H), 6.76 (s, 1H), 4.76 (s, 2H), 4.19 (s, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:32]2[CH:37]=[CH:36][C:35]([CH:38]([OH:40])[CH3:39])=[C:34]([O:41][CH3:42])[N:33]=2)=[CH:14]\[C@@H:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:43](=[S:45])=[S:44].[CH3:46]I>O1CCCC1.O>[C:43]([S:45][CH3:46])(=[S:44])[O:40][CH:38]([C:35]1[C:34]([O:41][CH3:42])=[N:33][C:32](/[C:13](/[C:10]2[CH:11]=[CH:12][C:7]([C:3]([CH3:4])([CH3:5])[CH3:6])=[CH:8][CH:9]=2)=[CH:14]/[C@H:15]2[CH2:16][CH2:17][C:18](=[O:31])[N:19]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])=[CH:37][CH:36]=1)[CH3:39]
Reactant: CI
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)O)c(OC)n2)c(OC)c1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)OC(=S)SC)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (22 mg, 60% in oil) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(1-hydroxyethyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (100 mg) in tetrahydrofuran (2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was warmed to room temperature and carbon disulfide (66.7 μL) was added, followed by stirring for 30 minutes. Methyl iodide (68.5 μL) was added and the mixture was stirred for 3.5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to give O-[1-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)ethyl] S-methyl carbonodithioate as a colorless oil (109 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=CC=C[N:12]=3)NC=2N=CN=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[NH:32][C:26]2[N:27]=[CH:28][N:29]=[C:30](O)[C:25]=2[CH:24]=1>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:16]=[C:11]([CH:9]=[CH:10][CH:3]=1)[NH:12][C:30]1[C:25]2[CH:24]=[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[NH:32][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: Oc1ncnc2[nH]c(-c3ccccn3)cc12
Reactant: Clc1ncnc2[nH]c(-c3ccccn3)cc12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccc(Nc2ncnc3[nH]c(-c4ccccn4)cc23)c1
Reaction time: 2 h

Procedure:
4-Chloro-6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]pyrimidine With the exclusion of moisture, 7.05 g (33.2 mmol) of 6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ol and 70 ml of phosphorus oxychloride are heated at boiling for 2 hours. The dark-brown suspension is concentrated by evaporation to a residual volume of 20 ml. The residue is introduced in portions into water, neutralized with solid NaHCO3 and 0.2 liter of ethyl acetate is added thereto. Filtering and washing with hot THF yield the title compound; 1H-NMR (300 MHz, DMSO-d6): 13.2 (sb, 1H), 8.72 (d, J=7, 1H), 8.63 (s, 1H), 8.23 (d, J=11, 1H), 7.97 (t, J=11, 1H), 7.46 (dd, J,=7, J2 =11, 1H), 7.35 (s, 1H). Further product can be isolated from the filtrate and the THF washing solution, which is concentrated by evaporation, by partitioning between ethyl acetate/water and digesting in ethyl acetate/diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:18])[CH3:17])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[Cl:25]N1C(=O)CCC1=O.Cl>CC(C)=O>[Cl:25][C:3]1[C:4]2[N:10]3[CH2:11][CH2:12][CH2:13][C@@H:14]([NH:15][C:16](=[O:18])[CH3:17])[C@H:9]3[C:8]3[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=3[O:6][C:5]=2[CH:23]=[CH:24][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)N[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.4 %

Procedure:
To a solution of trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]-pyrido[1,2-d][1,4]oxazepin1-yl)acetamide (Structure 12 of Scheme II, where R1=H, R2=H, R3=Cl, R4=R5=H, R15=CH3, X=O) (0.63 g, 1.84 mmol) in acetone (15 mL) were added N-chlorosuccinimide (246 mg, 1.84 mmol) and 6N (aq) HCl (3.1 mL). The resulting suspension was stirred at room temperature for 20 h. A second amount of N-chlorosuccinimide (246 mg, 1.84 mmol) was added and subsequently the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with ethyl acetate (3×), washed with sat. (aq) NaHCO3 (3×), 10% (aq) NaCl (2×) and dried (Na2SO4). The solvents were removed under reduced pressure. The solid was purified by column chromatography (silicagel, toluene/ethanol=9/1). Subsequent purification by HPLC resulted in the title compound (137 mg, 36.4%). Data: 1H-NMR (400 MHz, CDCl3) 1.55 (m, 1H), 1.82 (m, 2H), 1.94-2.20 (m, 1H), 2.10 (s, 3H), 2.92 (m, 1H), 3.11 (td, J=12.6, 4.2, 1H), 4.39 (d, J=1.9, 1H), 4.86 (m, 1H), 7.02-7.36 (m, 6 ArH).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]=[CH2:10])[C:3]=1[CH3:11].[Cu][C:13]#[N:14].C(N)CN.O>CN1CCCC1=O>[C:13]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]=[CH2:10])[C:3]=1[CH3:11])#[N:14]
Reactant: N#C[Cu]
Reactant: C=CCc1cccc(Cl)c1C
Solvent: O
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: C=CCc1cccc(C#N)c1C
Temperature: 190 °C
Reaction time: 14 h
Yield: 50.9 %

Procedure:
30 g of 1-chloro-2-methyl-3-prop-2-enylbenzene are dissolved in 150 ml of N-methylpyrrolidone, and 25 g of copper(I) cyanide are added. The reaction mixture is heated at 190° C. for 30 hours while stirring. After the mixture has been cooled to 20° C., 125 ml of ethylenediamine and 300 ml of water are added. Stirring is then carried out for 1 hour at 50° C. and for 14 hours at 20° C. Working up is effected by extracting with diethyl ether, washing the organic phase and drying over sodium sulfate, removing the drying agent and distilling off the organic solvent. 24.5 g of crude product are obtained. After chromatography (silica gel/toluene), 14.4 g of pure 1-cyano-2-mehtyl-3-prop-2-enylbenzene are isolated.