Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C[N:37]1[CH:41]=[C:40]([CH2:42][C:43](O)=[O:44])[N:39]=[CH:38]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:40]4[N:39]=[CH:38][NH:37][CH:41]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Cn1cnc(CC(=O)O)c1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)Cc4c[nH]cn4)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using (1-methyl-1H-imidazol-4-yl)-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.88 (s, 1H), 8.12 (d, 1H), 8.02 (s, 1H), 7.44 (s, 1H), 7.20 (dd, 1H), 7.10 (d, 1H), 5.82 (m, 1H), 4.70 (m, 1H), 4.18 (m, 1H), 4.06 (m, 2H), 3.36 (m, 1H), 2.84 (m, 2H), 2.30 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C27H29N7O2, 484.2 (M+H). found 484.2.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]>C(O)C>[Cl:5][C:6]1[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 89 %

Procedure:
4.3 g of cyclopropylamine are added dropwise to a solution of 24.9 g of ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-acrylate (5) in 80 ml of ethanol, while cooling with ice and stirring. When the exothermic reaction has subsided, the mixture is stirred for a further hour at room temperature, the solvent is stripped off in vacuo and the residue is recrystallised from cyclohexane/petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6) of melting point 89° to 90° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.Cl[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]=3)[CH:8]=2)[O:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)nc1
Temperature: 55 °C
Reaction time: 80 h

Procedure:
A solution of 233 mg (1.09 mmol) of 2,2,4,4-tetramethyl-6-ethynylchroman (Compound 2) and 209 mg (1.09 mmol) of ethyl 6-chloronicotinate (Compound 29) in 1 ml of triethylamine was degassed and then treated under argon with a powdered mixture of 50 mg (0.26 mmol) of cuprous iodide and 100 mg (0.14 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was heated under argon at 55 degrees C. for 80 h and then cooled to room temperature. The triethylamine was then removed under vacuum and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a yellow oil. PMR (CDCl3): δ1.36 (12H, s), 1.42 (3H, t, J-7.2 Hz), 1.85 (2H, s), 4.37 (2H, q, J-7.2 Hz), 6.79 (1H, d, J-.4 Hz), 7.34 (1H, dd, J-8.4 Hz, 2.1 Hz), 7.56 (1H, d, J-8.7 Hz), 7.60 (1H, d, J-2.1 Hz), 8.27 (1H, dd, J-8.7 Hz, 2.4 Hz), 9.19 (1H, d, J-2.4 Hz). MS exact masss, m/e 363.1837 (calcd. for C23H25O3N, 363.1834).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]Br>C1(C)C(C)=CC=CC=1>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][CH2:28][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][CH2:11][O:12][C:13]=2[CH:18]=1
Reactant: Clc1ccc(Oc2ccccc2CCBr)c(OCCBr)c1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: Clc1ccc2c(c1)OCCN(Cc1ccccc1)CCc1ccccc1O2
Yield: 64 %

Procedure:
9.1 ml of benzylamine were added to a solution of 7.26 g of 2-(2-bromoethoxy)-1-[2-(2-bromoethyl)phenoxy]-4-chlorobenzene in 714 ml of xylene and the mixture was heated to reflux for 24 h. After cooling the precipitate was removed with suction, washed with toluene and the filtrate was evaporated to dryness. The residue was chromatographed over silica with toluene-ethanol (9:1) to yield 4,17 g (64%) of 3-chloro-7,8,9,10-tetrahydro-8-phenylmethyl-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine. Rf 0.7 (silica; toluene-ethanol 8:2).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([Cl:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:18])=[C:13]([Cl:22])[CH:12]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2Cl)CC1
Yield: 92.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)-2-chlorophenoxy)acetic acid (0.2 g, 0.62 mmol), prepared from the step 4, and 1-methylpiperazine (0.062 g, 0.62 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.231 g, 92.0% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][O:8][C:7]3[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:6]=3[C:5]=2[N:16]=1.O1CCCC1.[Br:22][C:23]([CH3:30])([CH3:29])[C:24]([N:26]=[C:27]=[O:28])=[O:25]>>[Br:22][C:23]([CH3:30])([CH3:29])[C:24]([NH:26][C:27](=[O:28])[NH:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][O:8][C:7]3[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:6]=3[C:5]=2[N:16]=1)=[O:25]
Reactant: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(Br)C(=O)N=C=O
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)NC(=O)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 20 h

Procedure:
A mixture of 1250 mg (4.20 mmol) of 2-amino-8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine in tetrahydrofuran (6.75 mL, 83.2 mmol) was mixed with 1.25 g (6.00 mmol, 1.42 eq.) of crude 2-bromo-2-methylpropanoyl isocyanate and stirred for 20 hours. The precipitate was filtered off, washed with ethyl ether and dried on air to give 2-Bromo-2-methyl-N-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)carbamoylpropanamide. Weight 2.21 g (75%). MS(ESI+): 488.0
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH2:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Br:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C@@H:6]([NH:21][C:26]1[C:27]([Br:31])=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](N)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](Nc1nc(Cl)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (R)-3-amino-3-(4-(tert-butyldimethylsiloxy)pheny)-propanoic acid ethyl ester (1.0 eq), 2,4-dichloro-5-bromopyrimidine (1.2 eq) and DIEA (1.2 eq) in DMF was stirred at 50° C. for 2 hr, and then the DMF was evaporated. The residue was dissolved in EtOAc, and the resulting solution was washed successively with 0.1 M H3PO4, sat. NaHCO3 and sat. NaCl. The EtOAc extracts were treated with MgSO4, filtered, and evaporated to give (R)-3-(5-bromo-2-chloropyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@H:5]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C@@H:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[Na+]>O1CCCC1.O>[C:19]([O:18][C:16]([NH:15][C@@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C@H:6]([OH:23])[C@@H:5]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:4]([OH:34])=[O:3])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)[C@H](NCc1ccc(OC)cc1)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN[C@@H](C(=O)O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
9 g of 4(S)-tert-butoxycarbonylamino-3(S)-hydroxy-2(R)-(4-methoxybenzylamino)-5-phenyl-pentanoic acid ethylester are dissolved in 300 ml of tetrahydrofuran and 22 ml of 1 N aqueous sodium hydroxide solution are added. The reaction mixture is stirred for 16 hours at room temperature and diluted with 300 ml of water. Tetrahydrofuran is evaporated and the aqueous solution is washed with ethyl acetate. Acidification with 1N HCl leads to a white precipitate which is filtered off and dried (m.p.: 203°-206°).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]1([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Br[Mg]c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: C1=C(c2ccccc2)Cc2ccccc21
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A solution of 2-indanone (13.47 g, 102 mmol) in anhydrous benzene (100 mL) is added to phenylmagnesium bromide (3.0M in diethyl ether, 50.9 mL, 153 mmol) at 5° C. over 2.5 hours. The reaction was allowed to warm to room temperature over 30 minutes. The solution was cooled to 0° C. and 150 mL of water are added. The resultant mixture was diluted with 200 mL of hexanes, neutralized with 5M HCl, and washed with brine (2×100 mL). The aqueous layer was extracted with hexanes (2×50 mL), and the combined organic layers were dried (MgSO4), filtered, and the solvent removed in vacuo from the filtrate to yield a brown oil. This oil and p-toluenesulfonic acid (0.50 g) were dissolved in benzene (250 mL) in a round-bottom flask below a Soxhlet extractor containing 4 Å molecular sieves. After refluxing for 2.5 hours, the solution was filtered and cooled to 5° C. overnight. The product, a white flaky solid, was collected by filtration, and was washed with 50 mL of cold benzene. Additional product is obtained by concentrating the filtrate, cooling, and filtering the crystals (12.60 g, 64.3% yield). 1H NMR (400 Mhz, 20° C., CDCl3) δ7.62 (d,J=7.3 Hz, 2H), 7.47 (d,J =7.3 Hz, 1H), 7.39 (m, 3H), 7.27 (m, 2H), 7.22 (s,1H), 7.18 (t,J=7.4 Hz,1H), 3.78 (S, 2H). 13C{1H} NMR (100 Mhz, 20° C., CDCl3): δ146.3, 145.3, 143.1, 135.9, 128.6, 127.5, 126.5, 126.4, 125.6, 124.7, 123.6, 120.9, 38.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])(=[O:15])=[O:14]>N1C=CC=CC=1>[I:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:13]([CH3:12])(=[O:15])=[O:14])(=[O:24])=[O:23])[CH:3]=2)[NH:7][N:6]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2[nH]nc(I)c2c1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(I)c2c1
Yield: 82.4 %

Procedure:
N-(3-Iodo-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 25.7 g of 5-amino-3-iodo-1H-indazole, 440 ml of pyridine and 25.3 g of 2-(methylsulfonyl)benzenesulfonyl chloride. 39 g of N-(3-iodo-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a brown solid (mass analysis: Cl: m/z 478 (M+H)+, m/z 495 (M+NH4)+, m/z 260 (base peak)).
Reaction SMILES: C([O:4][C@@:5]1([C:13]#[CH:14])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)(=O)C.[H-].[Na+].O>CO>[C:13]([C@:5]1([OH:4])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)#[CH:14]
Reactant: C#C[C@@]1(OC(C)=O)CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C#C[C@@]1(O)CN2CCC1CC2
Reaction time: 2 h
Yield: 98.6 %

Procedure:
The acetate 49 (179 g, 0.926 mol) was treated with a solution of NaH (60% dispersion in oil, 100 mg, 2.7 mmol) in methanol (900 ml). After stirring for 2 hours at reflux, water (20 ml) was added and the solution concentrated. The residue was treated with ether and the white solid obtained was filtered off, dissolved in ethanol (2 L) and water (200 ml). The mixture was evaporated to dryness and dried under vacuum to give the (3R)-3-ethynyl-1-azabicyclo[2.2.2]octan-3-ol 50 as a white solid (138 g, 98%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][CH:9]1[C:15]([NH:28][C@@H:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=1)[CH3:27])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: O=C(O)C1COCC(=O)N1Cc1ccccc1
Product: COc1cccc([C@@H](C)NC(=O)C2COCC(=O)N2Cc2ccccc2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-7 by using 4-benzyl-5-oxomorpholine-3-carboxylic acid (Organic and Bio-Organic Chemistry (1972-1999); (1985); 2577-2580) and (R)-1-(3-methoxyphenyl) ethanamine. m/z 369.2.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=[C:39]4/[C:40](=O)[NH:41][C:42](=O)[NH:43]/4)=C3N=C(S(C)(=O)=O)N=2)CC1.N1C=CN=C1>C(O)(C)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7]([N:41]3[CH:40]=[CH:39][N:43]=[CH:42]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: c1c[nH]cn1
Solvent: CC(C)O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(-n4ccnc4)nc23)N1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (10 mg, 0.028 mmol) was mixed with imidazole (6 mg, 0.084 mmol) in isopropanol (1 mL). The mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature and the resulting solid was filtered off and washed with isopropanol. The solid was dried under vacuum to provide (Z)-5-((4-(cyclopropylamino)-2-(1H-imidazol-1-yl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a yellow solid. LCMS (ES): >95% pure, m/z 352 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:15][C:16]1[N:21]2[N:22]=[C:23]([CH2:25][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:24]=[C:20]2[C:19]([CH3:45])=[N:18][CH:17]=1>>[CH:13]1([N:9]([C:4]2[N:5]=[C:6]([CH:7]=[CH:25][C:23]3[N:24]=[C:20]4[C:19]([CH3:45])=[N:18][CH:17]=[C:16]([CH3:15])[N:21]4[N:22]=3)[N:2]([CH3:1])[N:3]=2)[CH3:10])[CH2:11][CH2:12]1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(N2CCCC2)nc1C=O
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(C=Cc3nc(N(C)C4CC4)nn3C)nc12
Yield: 52.6 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (75 mg, 416 μmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (191 mg, 416 μmol, Eq: 1.00) as starting materials. Chromatography afforded Cyclopropyl-{5-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-methyl-amine (71 mg, 52.6%) as light yellow solid. MS: m/z=325.4 (M+H+), mp: 196.4° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:21][C@@H:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C@H:22]([NH:29][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)[CH:12]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(C=O)cc1-c1ccc2c(ccn2C)c1
Reactant: C[C@@H](N)c1ccccc1
Product: COc1ccc(CN[C@H](C)c2ccccc2)cc1-c1ccc2c(ccn2C)c1

Procedure:
The title compound was prepared from 3-(1-methylindol-5-yl)-4-methoxybenzaldehyde and (R)-α-methylbenzylamine according to general procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([O:32][CH3:33])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:37]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:42]=1>>[CH2:37]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:34][CH3:35])(=[O:10])=[O:9])=[C:15]([O:32][CH3:33])[CH:16]=2)=[O:21])=[CH:24][CH:25]=1)[CH3:42]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}benzoic acid, m/z (ES+): 517.32 (M+H+.), was prepared in analogy to example 26, steps 1 to 6. Step 5 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[N:23]1([CH:28]2[CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH:28]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cn(C2CNC2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
A solution of 75 mg (0.25 mmol) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-(1,2,3-triazol-1-yl)azetidine hydrochloride (99.7 mg, 0.625 mmol) in 3 ml of pyridine in the presence of 95 mg of DBU was heated at 75° C. overnight. The resulting suspension was evaporated to dryness and to the residue, water was added and the separated yellow solid was collected (99 mg, 98%), m.p. >330° C. (dec). 1H NMR (TFA) δ: 9.1 (s, 1H), 8.74 (s, 1H), 8.6 (s, 1H), 6.2-5.98 (m, 1H), 5.55-5.05 (m, 4H), 4.45-4.15 (m, 1H), 1.65-1.2 (m, 4H). Anal. calcd. for C18H16F2N6O3 : C, 53.74; H, 4.01; N, 20.88. Found: C, 53.63; H, 3.99; N, 20.20.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:19][C:18]([C@H:15]2[CH2:14][CH2:13][C@H:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:7][CH2:8]3)[CH2:17][CH2:16]2)=[O:20])=[CH:24][CH:23]=1
Reactant: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: Oc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 996 mg of trans-4-[trans-4-(4-pentenyl)-cyclohexyl]cyclohexanecarboxylic acid in 80 ml of methylene chloride was treated with 752 mg of p-fluorophenol, 61 mg of 4-(dimethylamino)pyridine and 1.03 g of dicyclohexylcarbodiimide and stirred at room temperature for 15 hours. The reaction mixture was subsequently filtered. The filtrate was evaporated and the residue obtained was purified by chromatography on silica gel with ethyl acetate/petroleum ether (vol. 3:97). Crystallization of the produce obtained (1.24 g) from 40 ml of hexane gave 757 mg of pure trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexanecarboxylic acid 4-fluorophenyl ester with m.p. (C-N) 70.3° C. and cl.p. (N-I) 158.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Cl:12]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1cc(Br)ccc1N
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 1-(2-amino-5-bromophenyl)ethanone (200 mg, 0.93 mmol) in CH2Cl2 (5 mL) was added N-chlorosuccinimide (125 mg, 0.93 mmol). The mixture was stirred at room temperature overnight. Analysis indicated that the reaction was incomplete; therefore, additional N-chlorosuccinimide (125 mg, 0.93 mmol) was added and the mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by CombiFlash (40 g column, 0-10% EtOAc/heptane) to afford 1-(2-amino-5-bromo-3-chlorophenyl)ethanone (206 mg, 89%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH:20]=[C:21]2[C:25](=[O:26])[O:24][NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.CO>O1CCCC1.[C].[Pd]>[C:22]([CH:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:29][CH:28]=1)[C:25]([OH:26])=[O:24])(=[O:27])[NH2:23]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2C(=O)NOC2=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(N)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 44.1 %

Procedure:
4-[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]benzilidene]-3,5-isooxazolidinedione (11.5 g, 29.3 mmol) synthesized according to the method described in WO95/18125 was dissolved in tetrahydrofuran (220 ml). 5% Palladium carbon (1.15 g) was added and the mixture was vigorously stirred under a hydrogen atmosphere (normal pressure) at room temperature for 13.5 hr. To the reaction mixture was added methanol (150 ml), and the catalyst was removed by celite filtration. The solvent was evaporated and the residue was suspended in 2.5N aqueous sodium hydroxide solution (50 ml) and washed with ethyl acetate. To the obtained aqueous layer was added 1N hydrochloride (150 ml) and the precipitated white solid was collected by filtration. The solid was washed with water and dried to give the title compound (5.10 g, yield 44%).