Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH:7]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][N:12]=2)[O:6]C1C1C=CC=CC=1)([CH3:3])[CH3:2].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].CCOCC>Cl.CO>[OH:6][CH:7]([CH2:8][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH:14]=[CH:13][N:12]=1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]
Reactant: COc1ccc2ccnc(OCC3CN(C(C)C)C(c4ccccc4)O3)c2c1
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc2ccnc(OCC(O)CNC(C)C)c2c1
Product: O=C([O-])/C=C\C(=O)O

Procedure:
1 g of 1-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-7-methoxy-isoquinoline is heated to 80° in 10 cc of 1 N hydrochloric acid for 10 minutes. The reaction mixture is extracted with ether. The ethereal phase is discarded, and the aqueous phase is made alkaline with potash, extracted with ether, the ether phase is dried over magnesium sulphate and concentrated, whereby a crystalline product is obtained which is treated in methanol with maleic acid. Ether is added, whereby 1-(2-hydroxy-3-isopropylaminopropoxy)-7-methoxyisoquinoline is obtained as hydrogen maleate. M.P. 144°-146°.
Reaction SMILES: [N:1]1([C:10]2([CH2:15][C:16]#[N:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH2:18][OH:19].C(OCC)(=O)C>C(O)C.CCCCCC>[OH:19][NH:18][C:16](=[NH:17])[CH2:15][C:10]1([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: NO
Reactant: N#CCC1(n2ccc3cccnc32)CCCC1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N=C(CC1(n2ccc3cccnc32)CCCC1)NO
Yield: 112.2 %

Procedure:
To a stirred solution of (1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetonitrile (399) (1.4 g, 6.21 mmol) in ethanol (50 mL) was added 50% aq. NH2OH (4 mL, 62.15 mmol) and the reaction mixture was heated at 60° C. for 16 h (TLC, 30% ethyl acetate in hexane, Rf=0.1). Ethanol was evaporated, water (50 mL) was added and the mixture was extracted with etylacetate (3×50 mL). The organic phase was thereafter dried and concentrated to get crude N-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamidine (400) (1.8 g, 112%) as an off-white sticky liquid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:3]3[N:4]([C:8]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)=[CH:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:22][CH2:21]1
Reactant: CSc1nccc(-c2cnc3c(Cl)nccn23)n1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1nccc(-c2cnc3c(N4CCN(C)CC4)nccn23)n1

Procedure:
To a solution of 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (from Example 44 supra) (1.36 g, 4.91 mmol) in iPrOH (100 mL) was added 1-methylpiperazine (0.64 g, 6.38 mmol) followed by diisopropylethylamine (0.82 g, 6.38 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (150 mL) and washed with water (3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 8-(4-methyl-piperazin-1-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine. (Yield 1.4 g, 83.7%). LC-MS: [M+H]+ 342.
Reaction SMILES: O.[NH2:2]N.CO[N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:26])=[CH:10][C:9]=1F.CO>C(Cl)(Cl)Cl>[NH:2]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([N:14]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:15]3=[O:26])[CH:10]=2)[CH:7]=[N:6]1
Reactant: CON=Cc1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Reactant: NN
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccncc1N1CCN(c2ccc3cn[nH]c3c2)C1=O
Temperature: 200 °C
Yield: 39.17 %

Procedure:
Hydrazine hydrate (5 mL) was added to solution of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde O-methyl-oxime (I-121b: 350 mg, 0.917 mmol) in 2-methoxy methanol (10 mL). The resulting mixture was heated to 200° C. and maintained for 2 days. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography on silica gel (4% MeOH in CHCl3), washed with ether and dried to afford 105 mg of the product (39.17% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:29][C:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)([OH:27])[CH3:28])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: COc1ccc(C2(C)CO2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with sodium hydride 60% (0.803 mg, 20.12 mmol) in DMF and stirred at RT for 10 min. To this was added 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.28 g, 6.4 mmol) and again stirred at RT for 1 h. 2-(4-Methoxyphenyl)-2-methyloxirane (1.5 g, 9.14 mmol) was added and the mixture stirred at RT overnight. Ice water was added and the mixture extracted with EtOAc (3×). The combined organic layers were washed with water (4×) and concentrated. The product was purified on silica gel (#100-200 mesh) using 0-5% MeOH:DCM as eluent. 1HNMR (DMSO, Oxalate salt) d (ppm): 7.40 (d, 2H), 7.35 (d, 1H), 7.15 (s, 1H), 6.86 (m, 3H), 4.30 (m, 2H), 4.18 (d, 1H), 4.0 (d, 1H), 3.80 (s, 3H), 3.40 (m, 3H), 2.90 (m, 1H), 2.82 (s, 3H), 2.38 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[CH:2][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Reaction time: 15 h
Yield: 57.3 %

Procedure:
To a 0.35M solution of 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.53 mmol) in THF was added pyridine (Aldrich, 0.21 mL, 2.63 mmol) followed by 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 122 mg, 0.58 mmol). The resulting mixture was stirred for 15 hours. A 1M aqueous solution of HCl (20 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (5-15% EtOAc in hexane) to yield 140 mg (58%) of 94 as a pale yellow solid.
Reaction SMILES: P(=O)(O)(O)O.C([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])CCC.[C:19](#N)[CH3:20].F[C@@H:23]1[C@@H](COC(=O)C2C=CC(C3C=CC=CC=3)=CC=2)OC(Cl)[CH2:24]1>O>[CH:15]1([NH:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:20][CH2:19]2)[CH2:16][CH2:17][CH2:18][CH2:24][CH2:23]1
Reactant: O=C(OC[C@H]1OC(Cl)C[C@@H]1F)c1ccc(-c2ccccc2)cc1
Reactant: CCCCN(CCCC)CCCC
Reactant: CC#N
Agent: O=P(O)(O)O
Solvent: O
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
Seventy mg of molecular sieves 4A was added to a stirred mixture of 62 mg of orthophosphoric acid, 52 μL of tri-n-butylamine and 0.7 mL of acetonitrile at room temperature, and the mixture was stirred in an ice-bath. To the mixture was added 70 mg of 2,3-dideoxy-3-fluoro-5-O-(4-phenylbenzoyl)-D-erythropentofuranosyl chloride, and the mixture was reacted at the same temperature for 1 day. Then, to the mixture were added 156 μL of tri-n-butylamine and then deionized water. The mixture was extracted with toluene three times. To the organic layer was added 48 μL of cyclohexylamine and the mixture was stirred for 30 min. The mixture was concentrated in vacuo, and acetone was added to form a precipitate, which was collected by filtration. The residue was washed with chloroform and dried in vacuo at room temperature to give a dicyclohexylamine of compound (29) as a white solid.
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[N:19]([CH3:20])[C:18]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.C1([O:34][C:35](=O)[NH:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)C=CC=CC=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:18]2[CH2:17][CH2:16][N:15]([C:35]([NH:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:34])[CH2:14][C:13]=2[CH:12]=1)=[O:10]
Reactant: Cn1c(C(=O)Nc2ccccc2N)cc2c1CCNC2
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Nc2ccccc2N)cc2c1CCN(C(=O)Nc1cccnc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (1.0 eq) in DMF was added Et3N (3.0 eq.) followed by Pyridin-3-yl-carbamic acid phenyl ester (1.0 eq). Reaction was stirred at room temperature for overnight. Reaction mixture was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated to dryness. Crude mass was then purified by silica gel column chromatography to afford N2-(2-aminophenyl)-1-methyl-N5-pyridin-3-yl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-2,5-dicarboxamide.
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+]([O-])=O)=[CH:5][N:6]=1.SC1S[C:13]([CH3:16])=[N:14][N:15]=1.C(N(CC)CC)C>O1CCCC1.ClCCl>[S:3]1[CH:4]=[CH:5][N:6]=[CH:2]1.[S:3]1[CH:16]=[CH:13][N:14]=[N:15]1
Reactant: Cc1nnc(S)s1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1cscn1
Product: c1csnn1
Yield: 116.8 %

Procedure:
2-Bromo-5-nitrothiazole (2.09 g) and 1.32 g of 2-mercapto-5-methyl-1,3,4-thiadiazole in 10 mL of tetrahydrofuran are stirred at room temperature overnight, triethylamine is added to neutrality, and stirring is continued. The precipitated solid is dissolved in dichloromethane, washed with water, and the organic layer evaporated to give crude product. The crude product is crystallized from ethyl acetate/hexane to give 1 g of desired thiazole-thiadiazole compound as an off-white solid.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.CON(C)[C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[CH3:37]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:30]([C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:38])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)(=[O:10])=[O:11])=[CH:13][C:14]=1[C:19]([F:21])([F:22])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1cccnc1C
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by procedure analogous to that described in Example 29 using N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide and N-methoxy-2, N-dimethyl-nicotinamide. 1H NMR: (400 MHz, CDCl3) δ 8.61 (m, 1 H), 8.26 (m, 1 H), 8.20 (m, 1 H), 8.17 (m, 1 H), 8.04-8.01 (m, 1 H), 7.67 (d, 1 H), 7.50 (m, 1 H), 7.18 (m, 1 H), 2.41 (s, 3 H). MS: (M+H)/z=490.0.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:21][C@@H:22]1[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>O.C1COCC1>[C@@H:22]1([N:21]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:33](=[O:36])[CH:34]=[CH2:35])[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24]
Reactant: CCCCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N(CCCCCCCCCCCCCC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
A solution of 85 mmol (9 g) of sodium carbonate in 25 ml of water is added to a solution of 13.7 mmol (4 g) of N-tetradecyl-β-D-glucopyranosylamine in 190 ml of THF. A solution of 26 mmol (2.0 ml) of acryloyl chloride in 20 ml of THF is added dropwise over one hour. The THF is evaporated off and the acylamidosugar is then extracted with 300 ml of ethyl acetate. The organic phase is washed with a saturated solution of NaHCO3, dried over MgSO4 and evaporated at reduced pressure.
Reaction SMILES: C([Li])CCC.Br[C:7](Br)=[CH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:26])C=O.C1C[O:30][CH2:29]C1>CCCCCC>[CH:10]1([CH2:9][C:8]#[C:7][CH:29]([OH:30])[CH2:26][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C=O)c1ccccn1
Reactant: BrC(Br)=CCC1CCCCC1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: OC(C#CCC1CCCCC1)CCc1ccccn1
Temperature: 25 °C

Procedure:
2 equivalents of a solution of n-butyllithium in hexane (1.4 M) are added at -78° C. to a solution of 0.1 mol of 1,1-dibromo-3-cyclohexyl-1-propene in THF. After warming to room temperature, the mixture is stirred for a further hour, then cooled to -78° C. and a solution of 0.]mol of 2-(2-pyridyl)propionaldehyde (prepared according to J. Pract. Chem. 19, 226 (1963)) is added. After warming to room temperature again, the mixture is poured onto ice and extracted with MTB. After drying, concentrating and chromatography on silica gel (EE/cyclohexane (1:1)) 20.4 g of the title compound are obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:25]([O:28][C:29]1([CH2:53][CH2:54][CH2:55][OH:56])[CH2:34][C:33]2[CH:35]=[CH:36][C:37]([O:39][CH:40]([CH2:42][CH2:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH3:41])=[CH:38][C:32]=2[O:31][C:30]1([CH3:52])[CH3:51])(=[O:27])[CH3:26].[CH3:57][S:58](Cl)(=[O:60])=[O:59]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:25]([O:28][C:29]1([CH2:53][CH2:54][CH2:55][O:56][S:58]([CH3:57])(=[O:60])=[O:59])[CH2:34][C:33]2[CH:35]=[CH:36][C:37]([O:39][CH:40]([CH2:42][CH2:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH3:41])=[CH:38][C:32]=2[O:31][C:30]1([CH3:51])[CH3:52])(=[O:27])[CH3:26]
Reactant: CC(=O)OC1(CCCO)Cc2ccc(OC(C)CCCc3ccccc3)cc2OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: c1ccncc1
Product: CC(=O)OC1(CCCOS(C)(=O)=O)Cc2ccc(OC(C)CCCc3ccccc3)cc2OC1(C)C
Temperature: 5 °C

Procedure:
To 1.823 g (4.15 mmole) dl-5-acetoxy-3-(3-hydroxypropyl)-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran was added 20 ml of pyridine, the mixture stirred under nitrogen to affect solution and cooled to 5° C. Methanesulfonyl chloride, 520 mg (4.56 mmole), was added, the resulting mixture stirred at 5°-10° C. for 20 minutes, then allowed to warm to room temperature and stirred for an additional 50 minutes. The mixture was concentrated in vacuo and the residual oil taken up in ethyl acetate, washed twice with water, once with brine and the organic layer dried over anhydrous magnesium sulfate. After evaporation of solvent in vacuo the desired product was obtained as an oil, 1.999 g.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=O)[CH2:13][O:14][CH3:15].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.[C:39]1([CH3:46])C(C)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:39]([O:8][C:6]([C:5]1[CH:9]=[CH:10][C:2]2[S:26][C:12]([CH2:13][O:14][CH3:15])=[N:11][C:3]=2[CH:4]=1)=[O:7])[CH3:46]
Reactant: COCC(=O)Nc1cc(C(=O)O)ccc1F
Reactant: Cc1ccccc1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2sc(COC)nc2c1
Temperature: 120 °C

Procedure:
A mixture of 3.0 g (11.7 mMol) of 4-fluoro-3-methoxyacetamido-benzoic acid and 2.1 g (5.2 mMol) of Lawesson's reagent was refluxed for 6 hours in 90 ml toluene, mixed with 1.0 g Lawesson's reagent and heated to 120° C. for another 6 hours. After the solvent was replaced with xylene the mixture was heated to 180° C. for a further 8 hours in a pressurised vessel. Then the solvent was distilled off in vacuo, the crude product obtained was purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=5:95) and evaporated down again. Yield: 2.1 g of yellow crystals (72% of theory), Rf value: 0.55 (silica gel; ethyl acetate/petroleum ether=3:7)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH3:32])=[N:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[N:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: CCOc1ccc(Br)cn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOc1ccc(-n2c(C)c(Sc3cccc(C(=O)OC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 5-bromo-2-ethoxypyridine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH:10]=[CH:9]1.C([O-])([O-])=O.[K+].[K+].[NH2:21][OH:22].Cl>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:10]2[CH2:11][CH2:12][CH2:13][C:8](=[N:21][OH:22])[CH2:9]2)[CH2:4][CH2:3]1
Reactant: O=C1C=CCCC1
Reactant: CN1CCNCC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(C2CCCC(=NO)C2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
N-Methylpiperazine (104.16 g, 1041.6 mmol, 1.0 eq.) was added dropwise to a solution of 2-cyclohexen-1-one (100.0 g, 1041.6 mmol, 1.0 eq.) in ethanol (300 ml), and the resulting mixture was stirred for 5 hours at RT. The reaction solution was diluted with ethanol (600 ml) and cooled to 0° C.; K2CO3 (172.48 g, 1249.9 mmol, 1.2 eq.) and NH2OH.HCl (86.7 g, 1249.9 mmol, 1.2 eq.) were added, and the mixture was stirred for 30 minutes at 0° C. and then heated to RT and stirred for a further 16 hours. The reaction mixture was filtered off over Celite and washed with ethanol (500 ml). The filtrate was concentrated under reduced pressure and the residue was taken up in THF (100 ml) and n-hexane (500 ml) and stirred for 3 hours. The resulting solid was filtered off and used in the next stage without being purified further. Yield: 54% (120.0 g, 568.7 mmol)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:12][O:13][N:14]=2)=[CH:29][CH:28]=1
Reactant: OCCCNc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2nonc2NCCCO)nc2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(3-hydroxypropyl)-amine (0.70 g, 0.27 mmol), potassium carbonate (0.472 g, 3.42 mmol) and 4-chlorophenacyl bromide (0.069 g, 0.29 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 166-169° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:26]4[CH:34]=[C:33](Cl)[N:32]=[CH:31][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]3[C:26]4[CH:34]=[C:33]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[N:32]=[CH:31][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[CH:17]=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)CC1

Procedure:
4-Methylpiperazine was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 24 to give the title compound (Procedure C); δH [2H6]DMSO 9.80(1H,s), 8.82(1H,s), 8.47(1H,s), 8.23(1H,s), 8.15(1H,s), 7.75(1H,d), 7.67(1H,d), 7.54(1H,s), 7.28(5H,m), 5.68(2H,s) 3.64(4H,m), 3.34(4H,m), 2.27(3H,s); m/z (M+) 451.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:10][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=1[O:4][CH2:3][C:2]([F:15])([F:16])[F:1])(=[O:27])=[O:26]
Reactant: OCCOc1ccccc1OCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccccc1OCC(F)(F)F

Procedure:
To a solution of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (210 mg) in methylene chloride (1 ml) were added triethylamine (186 μl) and methanesulfonyl chloride (83 μl) with stirring under ice cooling, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (2/1) as eluent to give 273 mg of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methansulfonate melting at 40.5°-42.0° C.