Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:21][NH2:22])=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[N:10][CH:11]=1)=O)C.CC[O-].[Na+].CC(O)=O.O>CCO>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[O:12][C:9]1[N:8]=[C:7]2[NH:21][NH:22][C:4](=[O:3])[C:6]2=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(Oc2ccc(F)cc2F)nc1NN
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c2nc(Oc3ccc(F)cc3F)ncc12
Yield: 78.9 %

Procedure:
A solution of 2-(2,4-difluoro-phenoxy)-4-hydrazino-pyrimidine-5-carboxylic acid ethyl ester (7.0 g) and NaOEt (21% in EtOH, 16.85 mL) in EtOH (56 mL) was heated to 55° C. for two hours. The reaction was cooled, and HOAc was added to adjust pH to around 5.0. Water was added until no more precipitation occurred, and the mixture was filtered. The precipitate was collected and dried under vacuum to give 6-(2,4-difluoro-phenoxy)-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one (4.7 g).
Reaction SMILES: Br[C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.Cl.[N:27]1([CH2:33][C:34]2[CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38][CH:39]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([CH2:33][N:27]6[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]6)[CH:35]=5)[C:3]([O:24][CH3:25])=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: CC1(C)OB(c2cccc(CN3CCCCC3)c2)OC1(C)C
Reactant: COc1cc2c(cc1Br)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccc(CN3CCCCC3)c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Temperature: 120 °C
Yield: 39.7 %

Procedure:
A mixture of Example 490 (0.05 g, 0.118 mmol), 3-(piperidin-1-ylmethyl)-phenylboronic acid pinacol ester hydrochloride (0.0478 g, 0.141 mmol), potassium phosphate (0.1 g, 0.471 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0082 g, 0.0071 mmol) was degassed under 3 cycles of nitrogen and vacuum. DME (1.2 mL) and water (0.3 ml) were added and the mixture was degassed as before. The mixture was heated to 120° C. under microwave irradiation in a sealed tube for 1 h. Water (15 mL) and DCM (15 mL) were added. The aqueous fraction was separated and extracted with DCM (2×10 mL). The combined organic fractions were filtered through a Whatman 1μ PTFE tube and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to give the title compound (0.0243 g, 40%) as a colourless solid. δH (CDCl3) 7.76 (1H, s), 7.45 (1H, s), 7.41-7.31 (2H, m), 7.30-7.25 (1H, m), 6.57 (1H, s), 5.28 (1H, s), 4.37-4.32 (2H, m), 4.21-4.16 (2H, m), 3.78 (3H, s), 3.54 (2H, s), 2.84 (2H, s), 2.49-2.37 (4H, m), 1.64-1.54 (4H, m), 1.48-1.35 (8H, m). LCMS (ES+) 519.3 (M+H)+, RT 2.32 minutes (Method 1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[C:23]2[O:27][N:26]=[C:25]([CH3:28])[CH:24]=2)[C:17]2[CH:44]=[C:45]([CH3:52])[C:46]([C:48]([F:51])([F:50])[F:49])=[CH:47][C:16]1=2)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:43][C:40]([F:41])([F:42])[C:32]1[CH:31]=[C:30]([CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=1)[CH2:29][N:22]([C:23]1[O:27][N:26]=[C:25]([CH3:28])[CH:24]=1)[C@H:18]1[CH2:19][CH2:20][CH2:21][NH:15][C:16]2[CH:47]=[C:46]([C:48]([F:51])([F:49])[F:50])[C:45]([CH3:52])=[CH:44][C:17]1=2
Reactant: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc(C(F)(F)F)c(C)cc32)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc(C(F)(F)F)c(C)cc32)on1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.6 %

Procedure:
Add trifluoroacetic acid (10 mL) to a solution of (S)-5-[(3,5-bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (140 mg, 0.458 mmol) in methylene chloride (5 mL) at 0° C. under nitrogen. Warm the mixture to room temperature, stir for 4 h and pour the mixture into saturated aqueous sodium bicarbonate solution (20 mL). Extract the mixture with methylene chloride (20 mL) and wash the combined organic extracts with brine (10 mL), dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure to provide the title compound as a colorless oil (90 mg, 76%), which is used in the next step without purification: ESI MS m/z 552 [C25H22F9N3O+H]+.
Reaction SMILES: C(Br)C#C.ClCCl.[OH-].[Na+].[N:10]1(CCO)[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[NH:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1
Reactant: OCCn1cnc2cnc3ccccc3c21
Agent: C#CCBr
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: c1ccc2c(c1)ncc1nc[nH]c12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Benzyltrimethylammonium chloride (0.436 g) and propargyl bromide (6.07 mL of 80%) were added with stirring to a mixture of dichloromethane (185 mL) and aqueous sodium hydroxide (60 mL of 50%). 2-(1H-Imidazo[4,5-c]quinolin-1-yl)ethanol (10.0 g, 46.9 mmol) was added to the resulting solution. The reaction mixture was stirred at ambient temperature for 21 hours at which time analysis by HPLC showed that starting material remained. An additional equivalent of propargyl bromide was added and the reaction mixture was stirred for an additional 46 hours. Water was added to the reaction mixture and the layers were separated. The aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water and with brine, dried over magnesium sulfate and then concentrated under reduced pressure to provide a dark brown solid. This material was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane) to provide 7.0 g of 1-[2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as a brownish solid.
Reaction SMILES: [H-].[Na+].C1COCC1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.[CH2:24]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]>O.CCOC(C)=O>[CH2:24]([O:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:10]2[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]2)=[CH:35][CH:36]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCOc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOc1ccc(CN2CCSCC(NC(=O)OC(C)(C)C)C2=O)cc1
Yield: 156.7 %

Procedure:
81 mg of sodium hydride as a 60% suspension in oil (2.03 mmol) are introduced at room temperature into a 25 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of THF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 1.1 g (2.34 mmol) of 4-butoxybenzyl bromide are then added. The medium is stirred for 16 hours, 20 ml of EtOAc and 20 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed with 10 ml of water. The organic phase is dried, filtered and then evaporated to dryness to give 1.3 g of crude product, which product is chromatographed on a silica cartridge (25 g) with a 90/10 heptane/EtOAc mixture. 420 mg of product 39 are recovered (yield=53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([OH:26])=O.Cl.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([N:34]1[CH2:33][CH2:32][C:31]2[C:36](=[CH:37][CH:38]=[C:29]([F:28])[CH:30]=2)[CH2:35]1)=[O:26]
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(-c2nc(C(=O)N3CCc4cc(F)ccc4C3)c3cc(F)ccc3n2)cc(OC)c1OC
Yield: 54.3 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 108 (54.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.92 and 3.07 (2t, 2H), 3.58 and 4.04 (2t, 2H), 3.76-3.3.77 (d, 3H), 3.86 and 3.91 (2s, 6H), 4.55 and 4.98 (2s, 2H), 6.95-7.41 (m, 3H), 7.65-7.85 (m, 3H), 7.99-8.05 (m, 1H), 8.23-8.28 (m, 1H); MS (ESI) m/z 492 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[O:5][CH2:6][CH2:7][N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24]C(=O)OC(C)(C)C)=[O:16])[CH:10]=[N:9]1.Cl>O1CCOCC1.C(OC(=O)C)C>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:15](=[O:16])/[CH:14]=[CH:13]/[C:11]1[CH:10]=[N:9][N:8]([CH2:7][CH2:6][O:5][C:4]2[CH:32]=[C:33]([F:35])[CH:34]=[C:2]([F:1])[CH:3]=2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(F)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(F)c2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (E)-tert-butyl (2-(3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (113 mg, 0.23 mmol) in dioxane (3 mL) was mixed with a 4 M solution of HCl in dioxane (2 mL). The mixture was stirred for 6 h at room temperature under a nitrogen atmosphere. The reaction mixture was then diluted with ethylaceate (15 mL). The salt was filtered, washed with EtOAc and dried overnight to 92 mg of the hydrochloric acid salt of (E)-N-(2-aminophenyl)-3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamide as an off-white solid. MS: 1H NMR (CD3OD) δ: 8.07 (s, 1H), 7.86 (s, 1H), 7.70 (d, J=15.4 Hz, 1H), 7.28-7.54 (m, 4H), 6.62 (d, J=15.7 Hz, 1H), 6.45-6.57 (m, 3H), 4.55 (t, J=5.2 Hz, 2H), 4.37 (t, J=5.2 Hz, 2H) ES+(M+Na)+: 407
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[O:14]C=CC=2)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:23].[K+].CC(O)C>CC(C)=O.O>[CH2:1]([N:8]1[C:12]([C:13]([OH:14])=[O:23])=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: FC(F)(F)c1cc(-c2ccco2)n(Cc2ccccc2)n1
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(C(F)(F)F)nn1Cc1ccccc1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
To a solution of 9.5 g (0.0325 mol) 1-benzyl-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole in 350 mL acetone was added 27.2 g (0.172 mol) potassium permanganate in 450 ml water. The reaction mixture was heated at 60° C. for 4 h. After cooling to room temperature 200 ml 2-propanol were added and the mixture was stirred over night, it was filtered through a Celite pad and washed with 1 l acetone. The filtrate was concentrated in vacuo down to 150 mL. The residue was dissolved in 20 mL 2M NaOH and 150 mL water. The resulting aqueous phase was washed twice with 70 ml ethyl ether and was then acidified with 30 ml 5M HCl solution. The suspension was extracted with 200 and 50 ml ethyl acetate (EtOAc). The combined organic extracts were washed with 30 mL water and 5 mL brine and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 with 1% acetic acid) to give 6.1 g (0.022 mol, 67%) of 2-benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid as a off-white solid. MS: M=271.1 (ESI+)
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[N:25][C:17]=3[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)c1cccnc1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=c1c2cccnc2c(-c2ccccc2)nn1-c1ccccc1
Reaction time: 7 h

Procedure:
A mixture of phenylhydrazine (5.0 g) and 2-benzoylnicotinic acid (3.25 g) in toluene was stirred at the reflux temperature for 7 hours. The solvent was then evaporated and the residue was purified by chromatography to give the crude product which, on trituration with diethyl ether, yielded the title compound as a yellow solid, 0.41 g, m.p. 173.5°-176.5° C.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH:30]([CH3:32])[CH3:31])[N:5]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[CH:9][CH:8]=1.[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][C@@H:4]([N:5]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[CH:11][CH:12]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OC)C(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](CO)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.8 g of N-valeryl-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine methyl ester is dissolved in 30 ml of THF, treated at 5° C. with 83 mg of lithium borohydride and stirred at room temperature for 24 h. The reaction mixture is then concentrated, treated with water and adjusted to pH 2 with hydrochloric acid, a white precipitate forming. The mixture is extracted with ethyl acetate, washed with water and brine, dried and finally separated by means of flash chromatography (CH2Cl2 -MeOH 5:1). FAB-MS: m/e=422 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:25][O:24][C:8]2([CH2:13][CH2:12][CH2:11][CH:10]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:9]2[CH3:23])[O:7]1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56].[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]1[CH2:6][O:7][C:9]2([CH3:23])[C:10]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56])([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:11][CH2:12][CH2:13][CH:8]2[O:24]1
Reactant: CC1C(S(=O)(=O)c2ccccc2)CCCC12OCCO2
Reactant: OCCCCCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CC12OCCOC1CCCC2(CCCCCCCCCCO)S(=O)(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A solution of n-butyl lithium (1.02 ml) was added dropwise to a solution of 304 mg of 1,1-(ethylenedioxy)-2-methyl-3-(phenylsulfonyl)-cyclohexane and 4 mg of triphenylmethane in 5 ml of THF at −78° C. under an argon stream. After stirring for 10 minutes, the reaction was effected at room temperature for 1 hour. HMPA (1 ml) was added to the reaction mixture. It was then recooled to −78° C., followed by the dropwise addition of a solution of 90 mg of 10-bromo-1-decanol in 2 ml of THF. After reaction at −20° C. for 2 hours, the reaction mixture was poured into a saturated solution of ammonium chloride. The resulting mixture was extracted with ethyl ether. The organic layer was washed with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 1,2-(ethylenedioxy)-3-(10-hydroxydecyl)-2-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of a colorless oil. Yield: 92%, TLC: (hexane-AcOEt: 6-4) Rf=0.2
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][N:24]=2)(=[O:22])=[O:21])=[N:7][C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:9][C:10]=1[CH2:11]O.P(Cl)(Cl)(Cl)(Cl)[Cl:39]>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][N:24]=2)(=[O:22])=[O:21])=[N:7][C:8]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:9][C:10]=1[CH2:11][Cl:39]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)c(Oc2c(CO)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cl)c(Oc2c(CCl)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Yield: 72.6 %

Procedure:
0.2 g of the compound obtained in Example 38 in 3.5 ml of POCl3 was stirred with 0.083 g of PCl5 at 20° C. for 2 hours. Thereafter, the POCl3 was distilled off and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate (sic). The organic phase was washed with water, dried and the solvent was evaporated. The residue was chromatographed over silica gel with chloroform-methanol, thereafter recrystallized from dichloromethane-ethanol. 0.150 g of 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-morpholin-4-yl-pyrimidin-4-ylamide, m.p. 205° C., was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[OH-].[Na+]>C(O)C>[C:14]([C:11]1[CH:12]=[C:13]2[C:8]([C:7]([CH3:18])=[N:6][N:5]2[CH2:4][C:3]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=2[Cl:1])=[CH:9][CH:10]=1)([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2c(C)nn(Cc3ccc(Cl)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2ccc(Cl)cc2Cl)c2cc(C(=O)O)ccc12
Temperature: 90 °C
Yield: 99.4 %

Procedure:
1-(2,4-Dichlorobenzyl)-6-(methoxycarbonyl)-3-methyl-1H-indazole (0.2 g, 0.57 mmol) was suspended in ethanol (10 ml), and a 1M aqueous sodium hydroxide solution (2 ml) was added. The mixture was stirred under heating at 90° C. for 40 min. After the starting compound disappeared, the ethanol was distilled away under reduced pressure. The residue was acidified with 1N hydrochloric acid (3 ml) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (0.19 g, 99%) as colorless crystals.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:2]1.C1COCC1.[Li]CCCC.[Si:32](Cl)([CH3:35])([CH3:34])[CH3:33]>CCCCCC.O>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:1]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:2]=2)([CH3:12])[CH3:11])=[CH:14]1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C1=CCc2ccccc21)C1=CCc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C1=CC([Si](C)(C)C)c2ccccc21)C1=CC([Si](C)(C)C)c2ccccc21
Temperature: 25 °C
Yield: 95.1 %

Procedure:
3.3 g of 2,2-bis(3-indenyl)propane (20511/46, MW 272.39, 12.11 mmol) and 50 m of THF in a 100 mL flask were cooled to -70° C. while stirring. 17 mL of a 1.6 M solution of BuLi (27.2 mmol) in hexane were added dropwise. At the end of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solution was cooled again to -70° C. and 3.4 mL of Me3SiCl (MW 108.64, d 0.856, 26.8 mmol) were added. At the end of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water is then added, the organic layer is separated and the water layer extracted twice with Et2O, all organic phases were combined and dried over MgSO4, then filtered and all volatiles removed in vacuo. 4.8 g (95%) of a mixture of rac/meso 2,2-bis(1-trimethylsilyl-3-indenyl)propane was obtained. 1H NMR (200 MHz, C2D2Cl4, 120° C., referenced to the peak of residual C2HDCl4 at 5.75 ppm): 7.1-7.3 (m, 4H, C6 ring), 6.75-6.95 (m, 4H, C6 ring), 6.3-6.4 (br s, 2H, C5 ring), 3.2-3.3 (m, 2H, C5 ring), 1.64, 1.62 (2 s, 6H, bridge methyls), -0.15, -0.17 (2 s, 18H, TMS methyls).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:5]2[O:6][C:2]([Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(Cc2ccc(Br)o2)CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN2CCN(C)CC2)o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A round-bottomed flask was charged with 1-((5-bromofuran-2-yl)methyl)-4-methylpiperazine (1.29 g, 4.88 mmol), and THF (20 mL). The solution was cooled to −78° C. in a dry ice/acetone bath. tert-Butyllithium (6.56 mL, 10.5 mmol; 1.6 M in pentane) was added, and the reaction mixture was stirred for 30 minutes. Tributylchlorostannane (1.12 mL, 4.15 mmol) was added the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched by adding pH 7 phosphate buffer (20 mL) and warming to room temperature. The reaction mixture was extracted with EtOAc (50 mL), washed with brine (2×50 mL), dried over sodium sulfate, filter and concentrate. Purify by Biotage 40S (EtOAc). Isolated product (1.20 g, 52%) as a green oil. 1H NMR (CDCl3, 400 MHz) δ 6.47 (d, J=3.1 Hz, 1H), 6.21 (d, J=2.3 Hz, 1H), 3.62 (s, 2H), 2.50 (br s, 8H), 2.27 (s, 3H), 1.53 (m, 6H), 1.33 (m, 6H), 1.06 (m, 6H), 0.88 (m, 9H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[NH2:9][C:10]1[C:15]([N:16]([CH3:18])[CH3:17])=[N:14][C:13]([Br:19])=[CH:12][N:11]=1.[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32](Cl)(=[O:34])=[O:33].CCOCC>O1CCCC1>[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32]([NH:9][C:10]1[C:15]([N:16]([CH3:17])[CH3:18])=[N:14][C:13]([Br:19])=[CH:12][N:11]=1)(=[O:34])=[O:33]
Reactant: CN(C)c1nc(Br)cnc1N
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)c1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: -60 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A 2M solution of lithium diisopropylamide in tetrahydrofuran (THF)/heptane (1:1 v/v; 2.3 ml) was added over 10 minutes to a stirred solution of 2-amino-5-bromo-3-dimethylaminopyrazine (0.45 g) in dry THF (25 ml) at -60° C. The solution was stirred at -60° C. for 1 hour and then 5-dimethylamino-1-naphthalenesulphonyl chloride (0.62 g) was added portionwise over 5 minutes. The solution was allowed to warm to ambient temperature and then stirred for 18 hours. Ether (20 ml) was added and the solution was extracted with water (2×20 ml). The aqueous extracts were neutralised to pH 7 with 10% citric acid solution and extracted with ethyl acetate (2×20 ml). The organic extracts were combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting solid was further purified by elution with dichloromethane through a fresh silica gel Mega Bond Elut column to give 5-dimethylamino-N-(5-bromo-3-dimethylamino-2-pyrazinyl)-1-naphthalenesulphonamide (0.125 g), m.p. 180-182° C. (after trituration with ether); mass spectrum (+ve FAB, methanol/dichloromethane/DMSO/NBA): 450 (M+H)+.