Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:21]=[CH:22][N:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.CCCCC.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[C:48](Cl)=[O:49]>C1COCC1>[C:27]1([S:24]([N:20]2[CH:21]=[C:22]([C:48]([C:47]3[CH:51]=[C:52]([O:56][CH3:57])[C:53]([O:54][CH3:55])=[C:45]([O:44][CH3:43])[CH:46]=3)=[O:49])[N:23]=[C:19]2[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=S(=O)(c1ccccc1)n1ccnc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)n2)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of 1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole (10ya) (5.0 mmol) in anhydrous THF (100 mL) at −78° C. was added 1.7 M tert-butyllithium in pentane (1.2 equiv, 6.0 mmol) and stirred for 10 min. A solution of 3,4,5-trimethoxybenzoyl chloride (1.2 equiv, 6.0 mmol) in THF was added at −78° C. and stirred overnight.2 The reaction mixture was quenched with 100 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (300 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 3:1) to give a white solid. Yield: 30%. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=10 Hz, 1H), 8.04 (d, J=10 Hz, 2H), 7.91 (s, 1H), 7.76 (d, J=5 Hz, 2H), 7.65 (t, J=10 Hz, 1H), 7.55-7.58 (m, 5H), 7.40 (s, 2H), 7.33-7.36 (m, 3H), 7.25 (t, J=10 Hz, 1H), 4.05 (s, 3H), 4.03 (s, 6H). MS (ESI) calcd for C33H27N3O8 657.0. Found 680.1 [M+Na]+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][C@@H:42]([C@@H:73]([NH:81][C:82]([O:84][CH2:85][C:86]1[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=1)=[O:83])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:43][C:44]([NH:46][C@H:47]1[CH2:51][CH2:50][N:49]([C:52]([C@@H:54]2[CH2:58][C@H:57]([SH:59])[CH2:56][N:55]2[C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=2)=[O:61])=[O:53])[CH2:48]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:59][C@@H:57]3[CH2:56][N:55]([C:60]([O:62][CH2:63][C:64]4[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=4)=[O:61])[C@H:54]([C:52]([N:49]4[CH2:50][CH2:51][C@H:47]([NH:46][C:44](=[O:45])[CH2:43][C@@H:42]([OH:41])[C@@H:73]([NH:81][C:82]([O:84][CH2:85][C:86]5[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=5)=[O:83])[CH2:74][C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=5)[CH2:48]4)=[O:53])[CH2:58]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)C[C@@H](O)[C@H](Cc5ccccc5)NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 81.6 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carbapen-2-em-3-carboxylate (1.40 g) and (2S,4S)-2-[(3S)-3-[(3R,4S)-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)amino-5-phenylpentanoylamino]-pyrrolidin-1-ylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.80 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl)-2-[(2S,4S)-2-[(3S)-3-[(3R,4S)-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)amino-5-phenylpentanoylamino]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)-pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (2.13 g) was obtained as an amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CC(C)=O>[C:1]([O:5][C:6]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([O:17][S:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:16][C:10]=2[N:9]=1)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(O)ccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
5.98 g of (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester were combinated with 4.67 g of 4-fluorobenzenesulfonyl chloride and 6.75 ml of trietylamine in 100 ml acetone. The reaction mixture was stirred at room temperature for 1 hour. Solvents were evaporated under reduced pressure yielding 6.45 g crude 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-1H-benzoimidazol-5-yl ester.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13]>O>[NH2:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Cl:3])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
46.0 g (0.3 mol) of phosphorus oxychloride was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd. ) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 100 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 100 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 9.3 g (0.055 mol) of a white crystal of 2-amino-6-chloropurine (yield 55%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([CH3:13])=[CH:5][C:4](=[O:14])[CH2:3]1.[OH:16]O.[OH-].[Na+].Cl>CO>[CH3:15][C:2]1([CH3:1])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]2([CH3:13])[O:16][CH:5]2[C:4](=[O:14])[CH2:3]1
Reactant: OO
Reactant: CCOC(=O)C1C(C)=CC(=O)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1C(C)(C)CC(=O)C2OC21C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5 g of 3,3,5-trimethyl-4-ethoxycarbonyl-5-cyclohexen-1-one [which can be prepared according to the method described in Example 1] in 800 ml of methanol were cautiously mixed with a solution of 24 ml of a 30% solution of H2O2 and 6 ml of a 6N solution of NaOH. The reaction mixture, after having been stirred for 2 days at room temperature, was neutralized with a diluted HCl solution and the volatile portions were separated by evaporation. Distillation of the residue gave 3,3,5-trimethyl-4-ethoxycarbonyl-5,6-epoxy-cyclohexanone in a pure state.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:17]=[C:16]([CH3:18])[C:15](I)=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH2:32]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[CH2:32]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]([C:15]2[C:16]([CH3:18])=[CH:17][C:9]([N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:10]3[C:14]=2[CH2:13][CH2:12][CH2:11]3)[OH:45])=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1I)CCC2
Reactant: CC(C)c1cc(C=O)ccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1C(O)c1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a solution of dibenzyl(7-iodo-6-methylindan-4-yl) amine (583 mg) in dry tetrahydrofuran (10 mL) was added a 1.48 mol/L solution of tert-butyllithium in n-pentane (1.30 mL) at −100° C. The mixture was stirred for 15 min. Adding dropwise 4-benzyloxy-3-isopropylbenzaldehyde (320 mg) in tetrahydrofuran (5 mL), the reaction mixture turned orange solution. The reaction mixture was stirred at ambient temperature for 15 min, and then warmed to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride to quench the reaction. Adding brine, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethyl acetate=3/1−1/1) to give the title compound (497 mg).
Reaction SMILES: Br[CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4].C(N(CC)C(C)C)(C)C>ClCCCl>[C:14]([C:13]1[C:12]2[C:7](=[CH:8][C:9]([C:19]([O:21][CH3:22])=[O:20])=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH:2]=[CH:3][CH3:4])(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC=Cc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Yield: 39.6 %

Procedure:
To a solution of methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (179 mg) in 1,2-dichloroethane (8 ml) was added N,N-diisopropylethylamine (0.24 ml) and refluxed for 40 minutes. The resulting mixture was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with diluted hydrochloric acid, water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. Trituration with diethyl ether gave methyl 3-isobutyryl-2-(1-propenyl)indole-6-carboxylate (55.2 mg).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of butyl bromide and ethyl 4-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 4-butoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.57 (s, COOH); 7.85 (d, J=8.8, 2 arom. H); 6.98 (d, J=8.8, 2 arom. H); 4.02 (t, CH3CH2CH2CH2O); 1.69 (m, CH3CH2CH2CH2O); 1.43 (m, CH3CH2CH2CH2O); 0.92 (t, CH3CH2CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 166.99 (—C═O); 162.29; 131.32 (2 arom. C); 122.77; 114.17 (2 arom. C); 67.45; 30.58; 18.66; 13.63.
Reaction SMILES: [O:1]=[C:2]1[CH2:16][CH:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH:4]2[CH2:3]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[CH2:6]1[CH:5]2[CH2:16][C:2](=[O:1])[CH2:3][CH:4]2[CH2:8][NH:7]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC2CNCC2C1

Procedure:
tert-Butyl 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylate 1e (0.32 g, 1.42 mmol) was dissolved in 10 mL of dichloromethane with stirring. Upon cooling by an ice-water bath, trifluoroacetic acid (3.27 mL, 42.7 mmol) was added and the reaction mixture was reacted for 30 minutes at 0° C. The mixture was concentrated under reduced pressure to obtain the crude title compound hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f, which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][N:5]2[C:14]=1I.[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][N:5]2[C:14]=1[CH:35]([OH:36])[C:33]1[CH:32]=[CH:31][C:25]2/[C:26](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:37][C:21]=3[O:22][CH2:23][C:24]=2[CH:34]=1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: FC(F)(F)c1ccn2c(I)c(Cl)nc2c1
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(Cl)nc4cc(C(F)(F)F)ccn34)cc2COc2cc(F)ccc21
Yield: 90.6 %

Procedure:
[step 2] Using 2-chloro-3-iodo-7-(trifluoromethyl)imidazo[1,2-a]pyridine (1.81 g, 5.22 mmol) obtained in step 1 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (0.77 g, 2.6 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-{8-[(2-chloro-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (1.21 g, 90%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].N1C=CC=CC=1>C1COCC1>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:12]([C:11]1[CH:15]=[CH:16][C:8]([C:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][N:6]=2)=[CH:9][CH:10]=1)=[O:13]
Reactant: O=C1CCC(c2ccc(C(=O)Cl)cc2)=NN1
Reactant: Nc1ccccc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1CCC(c2ccc(C(=O)Nc3ccccc3F)cc2)=NN1
Yield: 38.5 %

Procedure:
120 mg (0.5 mmol) of 4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)benzoyl chloride from example I are stirred, at 60° C. for 2 hours, in 5 ml of THF together with 56 mg (0.5 mmol) of 2-fluoroaniline and 0.1 ml of pyridine. The mixture is cooled down and inspissated. The inspissation residue is purified on a silica gel column. The clean fractions are combined, inspissated, crystallized using methanol, filtered-off with suction and washed with methanol. This results in 60 mg of colorless crystals having a melting point of 242-244° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].I[CH3:25]>O>[C:3]([C:7]1[CH:8]=[C:9]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:12]=1[O:13][CH3:25])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1cc(N2CCCC2=O)cc(C(C)(C)C)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1c(C(C)(C)C)cc(N2CCCC2=O)cc1C(C)(C)C
Yield: 81.2 %

Procedure:
To a stirred mixture of 0.3 g (7.5 mmol) of 60% sodium hydride in a mineral dispersion previously washed with hexane, in 20 ml of dimethylsulfoxide, there was added 2 g (6.9 mmol) of 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-pyrrolidin-2-one. Gas evolution was observed. Twenty minutes later, 1 g (7 mmol) of iodomethane was added. The reaction mixture was stirred for thirty minutes and then diluted with 70 ml of water. The precipitated solid was collected by filtration and recrystallized from acetone-hexane to yield 1.7 g (5.6 mmol) of 1-(3,5-di-tert-butyl-4-methoxyphenyl)pyrrolidin-2-one, melting point 90°-91° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][NH:7][CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(O)[CH2:9]1.O>O1CCOCC1>[CH3:6][NH:7][CH:8]1[CH:9]=[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][CH2:14]1
Reactant: CNC1CCc2ccccc2C(O)(c2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CNC1C=C(c2ccccc2)c2ccccc2CC1
Yield: 76.6 %

Procedure:
9.2 ml of 18 N sulfuric acid were added to a refluxing solution of 4.62 g of the product of Step A in 90 ml of dioxane and the mixture was refluxed for 15 minutes and was then cooled. The mixture was poured into iced water and was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 2-8-1 benzene-ethyl acetate-triethylamine mixture and then a 95-5-1 chloroform-methanol-triethylamine mixture to obtain 3.3 g of 7-methylamino-9-phenyl-6,7-dihydro [5H] benzocycloheptene.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C:16]([OH:18])=O)=[N:9][C:10]=2[O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:16]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:18])[CH2:24][CH:25]1[CH2:27][CH2:26]1)(=[O:22])[NH2:23]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(NC2CC2)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=359.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[F:33])[O:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([CH2:27][OH:28])=[CH:22][C:21]=1[F:29]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[F:33])[O:19][C:20]1[C:21]([F:29])=[CH:22][C:23]([CH2:27][O:28][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:24][C:25]=1[F:26]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(F)c(Cl)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and (4-(3-chloro-4-fluorophenoxy)-3,5-difluorophenyl)methanol (78 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=6[O:35][CH2:36]C=C)[CH:26]=[CH:27][CH:28]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:39])[C:15]=3[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C(OC(C)C)=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:46]([O:45][C@@H:40]([C:15]1[C:16]([CH3:39])=[N:17][C:18]2=[CH:22][C:21]3=[N:20][N:19]2[C:14]=1[C:11]1[CH:12]=[C:13]2[C:8]([O:7][CH2:6][CH2:5][CH:4]2[CH2:1][CH:2]=[CH:3][CH2:36][O:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:25]2[CH:24]=[C:23]3[CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:10]=1)[C:41]([O:43][CH3:44])=[O:42])([CH3:47])([CH3:48])[CH3:49]
Reactant: C=CCOc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4ccc5c(c4)C(CC=C)CCO5)n3n2)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1ccc2c(c1)C(CC=CCOc1ccccc1-c1cccc-3c1)CCO2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
A solution of (2S)-methyl 2-(7-(4-allylchroman-6-yl)-2-(2′-(allyloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.373 g, 0.567 mmol) in DCE (275 ml) was heated (70° C.) and then treated with Hoveyda-Grubbs cat.2nd gen. (0.025 g, 0.040 mmol). The reaction was stirred for 2.5 hrs, then additional catalyst (0.025 g, 0.040 mmol) was added, the temperature was raised (80° C.) and the reaction was stirred for 30 min. The reaction was cooled, concentrated, and the residue was purified by biotage (24 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexanes) to afford the desired product (0.300 g, 0.476 mmol, 84% yield). LCMS (M+H)=630.5.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:7][C:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:26][CH:25]=1)([C:13]([F:23])([F:22])[C:14](=[O:21])[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([F:12])([F:11])[F:10])=[O:6])([CH3:4])[CH3:3].[H-].[Na+].[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46]Br)=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[CH2:46]([N:7]([C:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:35])[F:36])=[CH:26][CH:25]=1)([C:13]([F:22])([F:23])[C:14](=[O:21])[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([F:10])([F:11])[F:12])[S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)S(=O)NC(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)N(Cc1ccccc1)C(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
A solution of Intermediate 103D (461 mg, 0.814 mmol) in anhydrous DMF (0.5 mL) was added to a suspension of NaH (65 mg, 1.627 mmol) (60% in mineral oil) at 0° C. After stirring for 5 min, BnBr (0.484 mL, 4.07 mmol) was added. The reaction mixture was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (4 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (260 mg, 44%) as a yellow gum. 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J=8.5 Hz, 2H), 7.33-7.27 (m, 3H), 7.14 (dd, J=7.3, 2.1 Hz, 2H), 6.80 (d, J=9.1 Hz, 2H), 4.46-4.38 (m, 2H), 4.00-3.95 (m, 2H), 3.72 (br. s., 1H), 3.51 (br. s., 1H), 3.35-3.10 (m, 2H), 2.37-2.25 (m, 2H), 2.09-1.99 (m, 2H), 1.70-1.39 (m, 6H), 1.34-1.29 (m, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23](O)[CH2:24][CH3:25])[CH:14]=[CH2:15].B(F)(F)F.CCOCC>O1CCOCC1>[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:24][CH3:25])[CH:14]=[CH2:15]
Reactant: C=CCOc1ccccc1C(O)CC
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=CCOc1ccccc1C(CC)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a flame-dried flask containing a near-solution of 4-hydroxycoumarin (337mg) and 1-(2-allyloxyphenyl)propanol of Preparation 36 (500 mg) in anhydrous dioxane (10 mL) under nitrogen is added boron trifluoride etherate (1.31 mL). The resulting solution is stirred at RT for 25 hrs. concentrated to remove solvent, diluted with aqueous sodium hydroxide (5%, 20 mL) and extracted with methylene chloride (2×25 mL). The organic phase is discarded and the aqueous phase is adjusted to pH 1 using 6M hydrochloric acid and extracted with methylene chloride (2×25 mL). The organic phase is washed with saline (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a viscous residue which is then chromatographed on silica gel (230400 mesh, 45g), eluting with a gradient of ethyl acetate/hexane (5/95-10/90). Pooling of fractions having an Rf =0.44 by TLC (ethyl acetate/hexane, 25/75) and removal of solvent gives the title compound.