Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:24])([CH3:23])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:24])([CH3:23])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:29]([C:28]4[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=4[O:26][CH3:25])=[O:30])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC)CC3)C(=O)C2(C)C)cc1O

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B11*HCl) and 2-methoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield 5-(3-hydroxy-4-methoxyphenyl)-2-{1-[(2-methoxyphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one as the product.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.BrC[C:24]([CH2:26][CH2:27][Cl:28])=[CH2:25]>C1COCC1>[Cl:28][CH2:27][C:26](=[CH2:1])[CH2:24][CH2:25][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:19]([OH:21])=[O:20]
Reactant: C=C(CBr)CCCl
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(CCl)CCC(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Step AAI (4): NaHMDS 2.0 M in THF (11.0 mL, 21.9 mmol) was added to a solution of 2-(4-fluorophenyl)acetic acid (1.50 g, 9.73 mmol) in THF (19.5 mL) at 0° C. The resulting mixture was stirred for 20 min at 0° C., then neat 2-(bromomethyl)-4-chlorobut-1-ene (1.96 g, 10.7 mmol) was added. After 10 min, the mixture was quenched with a water (5 mL) and concentrated in vacuo. The mixture was diluted with EtOAc and the organic layer was washed with 1N HCl, then brine, dried over sodium sulfate, and concentrated in vacuo to afford 5-(chloromethyl)-2-(4-fluorophenyl)hex-5-enoic acid. The titled product was used for subsequent chemistry without further purification. LC-MS (M−H)− 255.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24-7.41 (2 H, m), 6.96-7.11 (2 H, m), 4.91 (2 H, d, J=3.1 Hz), 3.82 (1 H, dd, J=8.7, 6.9 Hz), 3.60 (2 H, t, J=7.2 Hz), 2.84 (1 H, dd, J=15.0, 8.9 Hz), 2.39-2.55 (3 H, m).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[CH:16]=[C:15]([OH:17])[C:14]([CH:18]([CH3:20])[CH3:19])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10])[CH:4]=[CH2:5]>CO.O>[CH2:3]([O:6][C:7]1[CH:16]=[C:15]([OH:17])[C:14]([CH:18]([CH3:20])[CH3:19])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10])[CH:4]=[CH2:5]
Reactant: C=CCOc1cc(O)c(C(C)C)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc(O)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 88 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 2 ml) was added to a mixture of methyl 2-allyloxy-4-hydroxy-5-isopropylbenzoate (860 mg, 3.44 mmol) in methanol (12 ml) and water (4 ml) and the mixture was stirred and held at reflux for 5 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (30 ml). The solid material was collected by suction filtration, rinsed with water (2×20 ml) and sucked dry under reduced pressure to afford 2-allyloxy-4-hydroxy-5-isopropylbenzoic acid (715 mg, 88%) as a pale green solid. 1H NMR (DMSO-d6) 11.92 (1H, br s), 10.08 (1H, s), 7.56 (1H, s), 6.48 (1H, s), 6.03 (1H, m), 5.50 (1H, dm), 5.27 (1H, dm), 4.53 (2H, m), 3.11 (1H, m), 1.13 (6H, d). MS: [M+Na]+ 259.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[NH:14][C:15](=[O:35])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[NH:36][C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)=[CH:7][C:6]=1[NH:14][C:15](=[O:35])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[C:24]=1[O:33][CH3:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)c(OC)c1OC
Reactant: Nc1cnccn1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)Nc2cnccn2)ccc1C(C)(C)C)c1ccc(OC)c(OC)c1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,3,4-trimethoxyphenyl)octanamide (prepared as described in Preparation 74A) and 2-aminopyrazine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[F:55][C:56]1[CH:57]=[C:58]([OH:63])[CH:59]=[C:60]([F:62])[CH:61]=1>>[F:55][C:56]1[CH:57]=[C:58]([CH:59]=[C:60]([F:62])[CH:61]=1)[O:63][CH2:36][CH2:37][N:28]1[CH:29]=[CH:30][N:31]=[C:26]([N:23]2[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]2)[C:27]1=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1cc(F)cc(F)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Product: O=c1c(N2CCNCC2)nccn1CCOc1cc(F)cc(F)c1

Procedure:
The title compound was prepared according to the general procedure described above starting from TMAD (384 mg, 2.25 mmol), 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (600 mg, 1.86 mmol), triphenylphosphine (969 mg, 3.69 mmol), 3,5-difluorophenol (239 mg, 1.84 mmol). Yield: 123 mg (20%); mp 119-121° C. HRMS m/z calcd for C16H18F2N4O2 (M)+ 336.1398, found 336.1409.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[CH2:22]([N:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH3:23]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][CH2:28][CH2:27][CH2:26][CH2:25][N:24]([CH2:30][CH3:31])[CH2:22][CH3:23]
Reactant: CCN(CC)CCCCN
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CC)CCCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and N1,N1-diethylbutane-1,4-diamine (36.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 26.0 mg, (26% yield) MS (ES+): 394.2, (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16]CC)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].[O-]CC.[Na+].O>C(O)C>[CH2:30]([NH:29][C:27]([C:26]1[CH:32]=[CH:33][C:23]([N:20]2[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:13]([C:14]([OH:16])=[O:15])[N:22]=[N:21]2)=[CH:24][CH:25]=1)=[O:28])[CH3:31]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CCCCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 99.4 %

Procedure:
Ethyl 8-phenyl-3-oxooctanoate (1.01 g, 3.84 mmol, 1.23 eq.) obtained in Example 101a) and 4-azido-N-ethylbenzamide (purity 95%, 0.624 g, 3.12 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (290 mg, 3.84 mmol, 1.23 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.26 g, 3.10 mmol, 99.5%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:46])[C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]C)=[O:37])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=C[C:56]=1[NH:61][C@@H:62](CC1C=CC(C2C=CC=C(NC)C=2)=CC=1)C(OCC)=O)(=O)C1C=CC=CC=1.C(N(CC)C1C=CC(N=C=O)=CC=1)C>>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:46])[C:36]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([N:61]([CH3:62])[CH3:56])=[CH:43][CH:44]=3)=[O:37])[CH:30]=2)=[CH:27][CH:28]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)OCC)cc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(NC)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: CCN(CC)c1ccc(N=C=O)cc1
Product: CCOC(=O)[C@H](Cc1ccc(-c2cccc(N(C)C(=O)Nc3ccc(N(C)C)cc3)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Yield: 75 %

Procedure:
In a manner similar to the preparation of the ethyl (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionate (Example 1h), using 1.0 g (2.1 mmol) of ethyl (S)-2-(2-benzoylphenylamino)-3-(3′-methylaminobiphenyl-4-yl)propionate (Example 1g) and 0.40 g (2.47 mmol) of 4-(diethylamino)phenyl isocyanate, 0.86 g of ethyl (S)-2-(2-benzoylphenylamino)-3-{3′-[3-(4-dimethylaminophenyl)-1-methylureido]biphenyl-4-yl}propionate is isolated with a 75% yield. Melting point: 75° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[I:9]N1C(=O)CCC1=O>C(Cl)Cl>[I:9][CH2:1][C:2]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C1CCC(=O)N1I
Reactant: C=C1CCC(O)CC1
Solvent: ClCCl
Product: ICC12CCC(CC1)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a solution of 4-methylenecyclohexanol (1.88 g) in CH2Cl2 (37.6 mL) was added N-iodosuccinimide (4.5 g) under nitrogen atmosphere, which was stirred at ambient temperature for 3 hours. The resultant was washed with Na2S2O3 aq., H2O, and brine. The organic phase was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 1-(iodomethyl)-7-oxabicyclo[2.2.1]heptane (1.5 g) as colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]([C:9]1[C:10]([Cl:20])=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1)[CH2:7][CH3:8])=[O:5].CO.[OH-].[K+].[F:25][C:26]([F:31])([F:30])[CH2:27][CH2:28][SH:29]>O.C(OCC)(=O)C>[Cl:20][C:10]1[C:9]([N:6]([CH2:7][CH3:8])[C:4](=[O:5])[CH2:3][CH2:2][S:29][CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])=[CH:13][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1
Reactant: FC(F)(F)CCS
Reactant: CCN(C(=O)CCCl)c1cn(-c2cccnc2)nc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 20 °C

Procedure:
A 100 mL, 3-neck round bottom flask was charged with 3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide (500 mg, 1.60 mmol) and methanol (10 mL), potassium hydroxide (107 mg, 1.92 mmol) was added, followed by 3,3,3-trifluoro-propane-1-thiol (249 mg, 1.92 mmol) The mixture was heated at 50° C. for 4 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated the reaction was complete to give exclusively a new product. The reaction mixture was cooled to 20° C. and diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The organics were dried over sodium sulfate (Na2SO4) and concentrated to dryness to afford a light yellow oil, which solidified upon standing to give a light yellow solid (650 mg, quantitative).
Reaction SMILES: [CH3:1][Se:2][C:3]1[C:4]([NH2:48])=[N:5][C:6](=[O:47])[N:7]([CH:46]=1)[C@@H:8]1[O:38][C@H:12]([CH2:13][O:14][C:15]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:24][CH3:25])([O:22][CH3:23])[CH2:18][CH:17]=2)[C@@:10]([Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])([OH:11])[CH2:9]1.[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(OCC)(=O)C>CCCCCC>[C:49]([NH:48][C:4]1[C:3]([Se:2][CH3:1])=[CH:46][N:7]([C@@H:8]2[O:38][C@H:12]([CH2:13][O:14][C:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])([O:24][CH3:25])[CH2:20][CH:21]=3)[C@@:10]([Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41])([OH:11])[CH2:9]2)[C:6](=[O:47])[N:5]=1)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc([Se]C)c(N)nc3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccccc2)=CC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc([Se]C)c(NC(=O)c4ccccc4)nc3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccccc2)=CC1
Reaction time: 1 h

Procedure:
5-methylseleno-3′-t-butyldimethylsilyl-5′-O-(4,4-dimethoxytrityl)-2′-deoxycytidine (compound 2) 300 mg (MW 751.3, 0.4 mmol) was placed in a flask and dried on high vacuum for one hour before addition of anhydrous pyridine 10 ml. Benzoyl chloride 0.03 ml (0.6 mmol, 1.5 eq.) was added dropwise before the reaction solution was stirred for 1 hour. After the reaction was completed (monitored on TLC, 30% ethyl acetate in hexane, Rf=0.5), the crude product was extracted with saturated NaCl solution and ethyl acetate. The organic phase was removed and aqueous phase was extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous MgSO4, the salt was filtered, and the organic solvents were evaporated under reduced pressure. The residue was purified on a silica gel column (equilibrated with hexane) and eluted with an ethyl acetate/hexane gradient (EtOAc in hexane, 10-50%). Compound 3 was isolated and dried to afford a yellow-green solid 287 mg. (yield=84%). 1H-NMR (400 MHz, DMSO) δ: 0.09 and 0.04 [2×s, 6H, Si(CH3)2], 0.86 (s, 9H, t-butyl), 2.02 (s, 3H, SeCH3), 2.18-2.20 and 2.43-2.52 (2×m, 2H, H-2′), 3.29-3.33 and 3.43-3.46 (2×m, 2H, H-5′), 3.81 (s, 6H, 2×OMe), 4.05-4.08 (m, 1H, H-3′), 4.41-4.45 (m, 1H, H-4′), 6.30-6.34 (t, J=6.4 Hz, 1H, H-1′), 6.86-7.56 (m, 18H, arom-H), 7.88 (s, 1H, NH), 8.32 (s, 1H, H-6). 13C NMR (100 MHz, DMSO) δ: −4.89 and −4.69 [Si(CH3)2], 1.03 (SeCH3), 17.95 [SiC(CH3)], 25.73 [SiC(CH3)], 41.86 (C-2′), 55.26 (OMe), 63.05 (C-5′), 72.41 (C-3′), 86.30 (C-4′), 86.77 (C-5), 87.24 (C-1′), 113.27 (arom-C), 127.07 (arom-C), 128.13 (arom-C), 128.27 (arom-C), 129.38 (arom-C), 130.09 (arom-C), 132.67 (arom-C), 133.68 (C-6), 135.51 (NHCO), 144.41 (arom-C), 144.36 (C-2), 158.69 (C-4). HR-MS (ESI-TOF, negative ion mode): molecular formula, C44H51N3O7SeSi: [M−H]−: 840.2570 (calc. 840.2583)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH:38]([F:40])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:35][C@@H:34]4[C@@H](CN(C)C4)C3)=[O:27])[N:9]=2)[CH:7]=1.ClC1C=CC(OC(F)F)=C(C2[C:52](NC(C3C=NN4C=CC=NC=34)=O)=[CH:51][N:50]([CH2:65]C(O)=O)N=2)C=1.CN1CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH:38]([F:40])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:35][CH2:34][N:50]([CH3:65])[CH2:51][CH2:52]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CN1C[C@@H]2CN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)C[C@@H]2C1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN1CCNCC1
Product: CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1

Procedure:
The title compound was prepared in an analogous manner to cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide using {3-(5-chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid and methyl piperazine to afford the title compound as a pale yellow solid. LCMS (Method 5) [M+H]+=545.1, RT=2.89 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.85 (s, 1H), 8.78 (dd, 1H, J=1.6, 7.0 Hz), 8.71 (s, 1H), 8.56 (dd, 1H, J=1.7, 4.1 Hz), 8.41 (s, 1H), 7.69 (d, 1H, J=2.6 Hz), 7.41 (dd, 1H, J=2.6, 8.7 Hz), 7.28 (d, 1H, J=9.1 Hz), 7.00 (dd, 1H, J=4.2, 7.0 Hz), 6.47 (t, 1H, J=74.1 Hz), 5.04 (s, 2H), 3.72-3.65 (m, 2H), 3.57 (dd, 2H, J=4.8, 4.8 Hz), 2.47-2.39 (m, 4H), 2.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[OH2:10].[Mn]([O-])(=O)(=O)=[O:12].[K+]>N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:9]([OH:12])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1ccc(F)c(Br)n1
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(F)c(Br)n1
Temperature: 85 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
2-Bromo-3-fluoro-6-methylpyridine (3.60 g, 18.9 mmol) was dissolved in 10 mL of pyridine in pressure tube. To this was added 50 mL of water, and the mixture was warmed to 85° C. Potassium permanganate (5.99 g, 37.9 mmol) was added, the tube was capped, and the mixture was stirred at 85° C. for 48 hours. The mixture was filtered through GF/F filter paper, and the filtrate was concentrated to about half volume under reduced pressure. The remaining material was acidified to pH 4 with 1M aqueous HCl and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give 0.70 g of the title compound (17%).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C([Cl:18])=O>O1CCCC1.CN(C)C=O>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([Cl:18])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (10.0 g, 53.4 mmol) produced in Example A1(iii) in tetrahydrofuran (130 mL) were added oxalyl chloride (5.47 mL, 64.1 mmol) and N,N-dimethylformamide (2 drops), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyanocyclopropyl)benzoyl chloride as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](OC)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[OH:16][CH:17]([CH2:20][OH:21])[CH2:18][NH2:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:19][CH2:18][CH:17]([OH:16])[CH2:20][OH:21])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: NCC(O)CO
Reactant: COc1c([N+](=O)[O-])cc(Cl)cc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1NCC(O)CO

Procedure:
0.25 g of 4-chloro-2,6-dinitro-anisole (Kohn and Kramer, Monatsh, Chemie 49, 154) was dissolved in 2 ml of 2,3-dihydroxy-propylamine at 5° to 10° C. and stirred at this temperature for half an hour, whereupon the orange solution was pour on ice and the precipitated yellow crystals were filtered with suction. 0.2 g (64 Percent of the theoretical yield) of the dye was obtained, it had a melting of 82° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.ClC1C=CC(C=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[O:28][C:29]=2[CH3:35])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(Cl)cc3)oc2C)c2sccc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester (example 151 a]) was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared by conversion of the 4-chloro-benzaldehyde into 2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethanol in analogy to the sequence described in examples 21 a] to 21 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(7-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-(7-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-2-ethoxy-propionic acid as colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7](Cl)[N:6]=[N:5][C:4]=1[NH:10][NH2:11].[OH-].[Na+].[H][H]>CO.[Pd]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[N:5][C:4]=1[NH:10][NH2:11]
Reactant: [H][H]
Reactant: CNc1cc(Cl)nnc1NN
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1ccnnc1NN
Reaction time: 6.5 h

Procedure:
A solution of 10 g. of 4-methylamino-6-chloro-3-hydrazinopyridazine in 450 ml. of methanol and 150 ml. of 0.5 N sodium hydroxide in methanol are charged into a Paar shaker. To this solution, 2 g. of 10% palladium on carbon is added. The Paar shaker is charged with hydrogen at room temperature to an initial pressure of 50 psi and shaken. After about 6.5 hours, the reaction mixture is filtered, the solvent evaporated and the residue extracted with chloroform. The chloroform solution is evaporated to dryness and the 4-methylamino-3-hydrazinopyridazine obtained is dissolved in methanol. Hydrogen chloride gas is bubbled in, and the 4-methylamino-3-hydrazinopyridazine dihydrochloride (m.p. 247°-251°C.) which precipitates is collected by filtration.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:37]=[C:36]([CH3:38])[C:31]3[NH:32][C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:38][C:36]1[C:31]2[NH:32][C:33](=[O:35])[O:34][C:30]=2[CH:29]=[C:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:37]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)[nH]c12

Procedure:
64 mg (0.22 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 64 mg (0.221 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.174 mL (1.00 mmol) DIPEA were stirred overnight in 2.0 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.