Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[O:9][N:8]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[O:9][N:8]=[C:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: -15 °C
Yield: 95 %

Procedure:
168 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)-piperidinium hydrochloride obtained in step 1) above and 220 μl (3.1 eq.) of triethylamine were dissolved in 1 ml of dichloromethane and stirred at a temperature of −15° C. A solution of chloroacetyl chloride (40 μl, 1 eq.) in 1 ml of dichloromethane (CH2Cl2) was added dropwise to the resulting suspension. The resulting mixture was stirred at room temperature for 2 hours. 20 ml of dichloromethane were then added, and the resulting organic phase was washed with three times 50 ml of 5% hydrochloric acid and then dried over MgSO4, filtered and evaporated. 2-Chloro-1-[4-(3-thiophen-2-yl[1,2,4]oxa-diazol-5-yl)piperid-1-yl]ethanone was obtained in the form of a white solid, in a yield of 95%.
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[H-].[Na+].S(OC)(O[CH3:19])(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(O)C>[CH3:19][O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5]
Reactant: CCC=C(C)C(O)CCCCC
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC=C(C)C(CCCCC)OC
Temperature: 80 °C
Reaction time: 12 h
Yield: 75.8 %

Procedure:
5.0 g of 4-methyl-3-decen-5-ol dissolved in 25 ml of toluene are added dropwise over a period of 30 minutes at 80° C. while stirring to 1.54 g of a 55-60% sodium hydride dispersion in 25 ml of toluene. The mixture is stirred at 80° C. for 12 hours, cooled to 40° C. and treated dropwise with 5.6 g of dimethyl sulphate, the temperature again rising to 80° C. In order to complete the reaction, the mixture is stirred at 80° C. for a further 3 hours. After cooling to 40° C., 10 ml of ethanol are added thereto. The mixture is heated to boiling for a short period and then treated with cold 2N sodium hydroxide. The product is taken up in hexane, washed neutral, chromatographed on 250 g of silica gel in order to remove the oil of the sodium hydride dispersion used and the thus-obtained crude product is fractionally distilled. There are obtained 4.1 g (76% of theory) of 5-methoxy-4 -methyl-3-decene of boiling point 100°-105° C./14 Torr, nD20 =1.4337. Odour: very fresh, fruity, green, apple-like, blueberries, blackberries, herbaceous.
Reaction SMILES: BrN1C(C)(C)C(=O)N(Br)C1=O.C(=O)(O)[O-].[Na+].C(OOC(=O)CCCCCCCCCCC)(=O)CCCCCCCCCCC.[C:45]([O:48][C@@H:49]1[C@@:74]2([CH3:75])[C:53](=[CH:54][CH2:55][C@@H:56]3[C@@H:73]2[CH2:72][CH2:71][C@@:70]2([CH3:76])[C@H:57]3[CH2:58][CH2:59][C@@H:60]2[C@H:61]([CH3:69])/[CH:62]=[CH:63]/[C@H:64]([CH3:68])[CH:65]([CH3:67])[CH3:66])[CH2:52][C@@H:51]([O:77][C:78](=[O:80])[CH3:79])[CH2:50]1)(=[O:47])[CH3:46].N1C2C(=CC=CC=2)C=CC=1C>CCCCCC.C(OCCCC)(=O)C>[C:45]([O:48][C@@H:49]1[C@@:74]2([CH3:75])[C:53](=[CH:54][CH:55]=[C:56]3[C@@H:73]2[CH2:72][CH2:71][C@@:70]2([CH3:76])[C@H:57]3[CH2:58][CH2:59][C@@H:60]2[C@H:61]([CH3:69])/[CH:62]=[CH:63]/[C@H:64]([CH3:68])[CH:65]([CH3:66])[CH3:67])[CH2:52][C@@H:51]([O:77][C:78](=[O:80])[CH3:79])[CH2:50]1)(=[O:47])[CH3:46]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC
Agent: Cc1ccc2ccccc2n1
Solvent: CCCCCC
Solvent: CCCCOC(C)=O
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1

Procedure:
1,3-Dibromo-5,5-dimethylhydantoin (3.45 g, 12 mmol), sodium bicarbonate (400 mg) and lauroyl peroxide (50 mg) were added to a solution of (22E)-5,22-ergostadiene-1α,3β-diol diacetate (IX) (10.0 g, 20 mmol) in hexane (150 ml). The reaction solution was stirred under reflux for 25 minutes. After cooling, the crystals were separated by filtration from the reaction mixture and hexane was distilled off from a filtrate. The residue was dissolved in butyl acetate (80 ml) and added dropwise to a solution of quinaldine (14.3 g, 100 mmol) in butyl acetate (70 ml) with stirring under reflux. The mixture was further refluxed for 40 minutes. After cooling, the reaction mixture was washed successively with 2N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a crude (22E)-5,7,22-ergostatriene-1α,3β-diol diacetate (III) which was dissolved in chloroform (50 ml) and a solution of 4-phenyl-1,2,4-triazoline-3,5-dione (2.26 g, 13 mmol) in acetone (40 ml) was added dropwise with stirring at room temperature. After concentration of the reaction mixture, the resulting residue was purified by silica gel column chromatography eluting with 2/1 hexane/ethyl acetate to give 3.5 g of the foamy title compound (IV).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)[CH:24]=[N:25][CH:26]=1
Reactant: COc1cncc(Br)c1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: COc1cncc(N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)c1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 3-bromo-5-methoxy-pyridine.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.N[C:11]([O:13][CH2:14][CH3:15])=[O:12].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(N)=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N[Si](C)(C)C
Reaction time: 0.25 h
Yield: 129 %

Procedure:
15.6 ml of hexamethyldisilazane (0.075 mole) were added over 2 minutes to a refluxing mixture of 8.9 g (0.1 mole) of urethane, 183 mg (1 mmole) of saccharin and 10 ml of toluene and the theoretical amount of ammonia was evolved in 30 minutes. Refluxing was continued for 15 minutes and the solvent and excess hexamethyldisilazane were removed under reduced pressure. The residue was vacuum distilled to obtain 15.6 g (96.9%) of N-trimethylsilylurethane boiling at 73° C. at 12 mm Hg and nD 25=1.4268.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8](Cl)(=[O:10])=[O:9].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].O.C(OCC)(=O)C>ClCCl>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][S:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])(=[O:10])=[O:9]
Reactant: Cc1ccccc1CS(=O)(=O)Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)Cc2ccccc2C)c(OC)c1
Reaction time: 0.5 h

Procedure:
At room temperature, 1.00 g of o-tolylmethanesulfonyl chloride was initially charged in 30 ml of dichloromethane, and 1.46 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was stirred for 30 minutes. Then the mixture was admixed with 50 ml of water and 50 ml of ethyl acetate, and then the aqueous phase was washed once more with 30 ml of ethyl acetate. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. The residue (1.42 g) was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)(O)[O-].[Na+].Cl[CH2:19][C:20](=[O:22])[CH3:21]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][C:20](=[O:22])[CH3:21])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 100 °C

Procedure:
166 g (1 mol) of 3-methylxanthine and 110 g (1.3 mol) of sodium bicarbonate are suspended in 500 ml of dimethylformamide, the suspension is heated to 100° C., while stirring, and 111 g (1.2 mol) of chloroacetone are added dropwise over a period of 2 hours. The mixture is then subsequently stirred at 100° C. for two hours and thereafter cooled and the precipitate formed is filtered off with suction and washed five times with 50 ml of dimethylformamide each time. After the product has been taken up in warm 1N sodium hydroxide solution at 60° C., dilute hydrochloric acid is added until the pH reaches 9, the mixture is filtered hot with suction and the residue is washed with water until free from chloride, rinsed with methanol and dried at 80° C. in a drying cabinet.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([S:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].O>C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][CH:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH:34]=[O:35])=[N:3][CH:4]=2)=[CH:20][C:21]=1[CH3:26]
Reactant: CN(C)C=O
Reactant: Cc1cc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)ccc1Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)ccc1Cl
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
A solution of 2-bromo-5-[[(4-chloro-3-methylphenyl)thio](2,5-difluorophenyl) methyl]-4-methylpyridine (2.0 g, 4.4 mmol) in toluene (50 ml) was cooled to −78° C., and in an argon atmosphere, n-butyllithium (1.54 M hexane solution, 3.4 ml, 5.3 mmol) was added thereto. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and then N,N-dimethylformamide (409 μl, 5.3 mmol) was added. After stirring for 30 minutes at the same temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=95:5 was concentrated under reduced pressure to obtain the title compound (700 mg, 1.7 mmol, 40%) as a colorless oily substance.
Reaction SMILES: [N:1]1([CH:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[C:23]([Cl:39])=[CH:22][N:21]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:25][C:20]([NH:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:21][CH:22]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl
Yield: 8.4 %

Procedure:
7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (18.0 mg, 0.0000731 mol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (25.0 mg, 0.0000720 mol) and 10-Camphorsulfonic acid (17.0 mg, 0.0000732 mol) were dissolved in Isopropyl alcohol (3.0 mL, 0.039 mol) and the reaction was microwaved on 300 watts, 140° C. for 20 minutes. The mixture was then reduced under nitrogen. The crude residue was isolated and purified by Gilson prep HPLC to afford 3.35 mg (8%) of 2-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide. LC/MS (ESI): 557.18. 1H NMR (400 MHz, DMSO, d6) δ 7.60 (d, 1H, J=8.59 Hz), 7.26 (s, 1H), 7.00 (d, 1H, J=8.09 Hz), 6.76 (t, 1H, J=7.58 Hz), 6.48 (t, 2H, J=7.57 Hz), 6.40 (d, 1H, J=8.34 Hz), 6.18 (d, 1H, J=8.09 Hz), 3.17 (d, 2H, J=13.39 Hz), 2.90 (m, 2H), 2.61 (t, 1H, J=12.89 Hz), 2.45 (m, 4H), 2.03 (m, 1H), 1.95 (m, 3H), 1.81 (s, 6H), 1.50 (m, 2H), 0.66 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.O>CCO>[Cl:1][C:2]1[C:3]([N:27]([CH3:28])[CH3:29])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1COCCN1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CCl)cs3)c1)=N2
Solvent: CCO
Solvent: O
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CN4CCOCC4)cs3)c1)=N2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 8-chloro-4-[3-(4-chloromethyl-thiazol-2-yl)-phenyl]-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (89 mg) (Example 191a), morpholine (0.17 mL) and KI (3 mg) in EtOH (0.5 mL) was stirred at 60° C. for 3 h. H2O (25 mL) was added to the cooled solution and the precipitate was collected by filtration and purified by chromatography on silica gel using AcOEt/acetone (1:1) as eluent. The product was stirred with 20% aqueous MeOH (20 mL) The pH of the mixture was set to 11 by addition of 1N NaOH and the solid was subsequently isolated by filtration to give the title compound (55 mg) as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)nc5)cc34)cn2)c1
Yield: 62.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperidine-1-carboxylate (96 mg, 0.173 mmol) was deprotected in methanol/HCl in dioxane (5/5 ml) to afford 49 mg (63% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 9.178-9.170 (d, 1H), 8.78-8.74 (dd, 1H), 8.71-8.66 (dd, 2H), 8.26 (s, 1H), 7.99 (s, 1H), 7.95-7.92 (d, 1H), 7.77 (s, 1H), 7.40-7.31 (q, 1H), 7.10-7.08 (d, 1H), 7.03-6.96 (m, 2H), 5.42 (s, 2H), 3.63-3.59 (d, 2H), 3.55-3.40 (m, 1H), 3.30-3.19 (m, 2H), 2.32-2.08 (m, 4H). MS: m/z=453.5 (M+1), HPLC: 93.40% in method A.
Reaction SMILES: CC(=[N:4][N:5]1[CH:9]=[N:8][NH:7][C:6]1=[O:10])C.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1>C(#N)C>[NH2:4][N:5]1[CH:9]=[N:8][N:7]([C:21]2[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=2)[C:6]1=[O:10]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC(C)=Nn1cn[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(-n2ncn(N)c2=O)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
A mixture of 7.0 g (0.05 mol) of 4-(1-methyl-ethylideneamino)-2 4-dihydro-3H-1,2,4-triazol-3-one, 21 g (0.15 mol) of potassium carbonate, 11.0 g (0.05 mol) of 4,6-dimethoxy2-methylsulphonyl-pyrimidine and 100 ml of acetonitrile is refluxed for 3 hours. After the mixture has cooled, it is filtered and the filtrate is concentrated, the residue is taken up in 100 ml of ethanol/water (vol. 1:1), and the mixture is stirred for 3 hours at 60° C. after 1 ml of concentrated hydrochloric acid has been added. The mixture is concentrated, the residue is then triturated with ethanol, and the product obtained in the form of crystals is isolated by filtering off with suction. 9.7 g (82% of theory) of 4-amino-2-(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 238° C. are obtained.
Reaction SMILES: C([O:3][C:4](=[O:30])/[CH:5]=[C:6](\[CH3:29])/[CH:7]=[CH:8]/[C@@H:9]1[CH2:11][C@@:10]1([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]=2[CH:23]=1)[CH3:12])C.CO.[OH-].[Na+].C(OCC)(=O)C>CCCCCC.C(#N)C.O>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:15]1[C:16]2[O:20][CH2:19][C:18]([CH3:21])([CH3:22])[C:17]=2[CH:23]=[C:13]([C@@:10]2([CH3:12])[CH2:11][C@H:9]2/[CH:8]=[CH:7]/[C:6](/[CH3:29])=[CH:5]/[C:4]([OH:30])=[O:3])[CH:14]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@@H]1C[C@]1(C)c1cc(CC(C)(C)C)c2c(c1)C(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CC#N
Product: CC(/C=C/[C@@H]1C[C@]1(C)c1cc(CC(C)(C)C)c2c(c1)C(C)(C)CO2)=C\C(=O)O

Procedure:
Following General Procedure H and using 5-{(1S, 2S) 2-[7-(2,2-dimethyl-propyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl]-2-methyl-cyclopropyl}-3-methyl-penta-2E,4E-dienoic acid ethyl ester (Compound 11, 0.132 g, 0.32 mmol), 15 mL of methanol and 5M aqueous sodium hydroxide (2 mL) followed by flash column chromatography using 25% ethyl acetate in hexane as the eluent and preparative reverse phase HPLC using 12% water in acetonitrile as the mobile phase, the title compound was obtained (0.098 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([O:20]CC3C=CC=CC=3)=[O:19])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[C:12]3[CH:34]=[CH:35][CH:36]=[CH:37][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[C:12]3[CH:34]=[CH:35][CH:36]=[CH:37][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OCC(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A mixture of a solution of (±)-cis-2-(4-methoxyphenyl)-3-(benzyloxycarbonylmethyl)oxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (880 mg) in a mixed solvent of 10% aqueous sodium hydroxide solution (2 ml), water (15 ml) and ethanol (15 ml) is stirred at 50° C. for 30 minutes. After the completion of the reaction, ethanol is distilled off under reduced pressure. The aqueous layer is washed with ethyl acetate and acidified with acetic acid under ice-cooling, and then, saturated with ammonium sulfate. The precipitated crystal is collected by filtration, washed with water and dried to give (±)-cis-2-(4-methoxyphenyl)-3-(carboxymethyl)oxy-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (230 mg), m.p. 184°-188° C. (decomposed).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>>[C:10]([C:9]1[CH:12]=[C:5]([CH:6]=[CH:7][C:8]=1[O:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=1)[CH2:4][O:3][C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1)#[N:11]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)nc1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 5-(hydroxymethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15](=O)[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15]([C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])=[S:35])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=S)c1cc(Cl)ccc1OC
Temperature: 80 °C

Procedure:
To a solution of Example 6B (1.4 g, 3.7 mmol) in toluene (50 mL) was added Lawesson's reagent (1.6 g, 4 mmol) and the mixture was refluxed at 80° C. for 30 minutes. After cooling to room temperature, the mixture was diluted with EtOAc, washed with 10% solution of bicarbonate, brine and dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (2:1 Hexane-EtOAc) provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.89 (t, J=7 Hz, 3H), 1.25 (sextet, J=7 Hz, 2H), 1.36 (s, 9H), 1.76 (m, 2H), 3.74 (s, 3H), 4.25 (t, J=7 Hz, 2H), 7.06 (d, J=9 Hz, 1H), 7.35 (m, 2H), 7.45 (s, 1H); MS (ESI+) m/z 397 (M+H)+. Anal. calcd for C19H25ClN2OS2: C, 57.48; H, 6.35; N, 7.06. Found: C, 57.26; H, 6.17; N, 6.79.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:13]=[CH:14][CH:15]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:10]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(-c4ccccc4)c3)c2C)C1
Yield: 59 %

Procedure:
In analogy to the procedure described in example 14C] but with 2.8 eq of K3PO4, [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and phenylboronic acid gave (5-biphenyl-3-yl-1,4-dimethyl-1H-pyrazol-3-yl)-(3-diethylamino-pyrrolidin-1-yl)-methanone in 59% yield as yellow oil. MS: 417.1 (MH+).