Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].BrC[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21].[C:22](=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH3:19][O:18][C:15]1[CH:16]=[C:17]([CH:12]=[C:13]([O:20][CH3:21])[CH:14]=1)[CH2:22][O:4][C:3]1[C:2]([CH3:1])=[C:8]([OH:9])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CBr)c(OC)c1
Reactant: Cc1c(O)cccc1O
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(COc2cccc(O)c2C)cc(OC)c1
Yield: 13.3 %

Procedure:
2-Methyl resorcinol (0.07 g, 0.59 mmol), 4-bromomethyl-1,3-dimethoxybenzene (0.13 g, 0.55 mmol), potassium carbonate (0.09 g, 0.68 mmol) and 18-crown-6-ether (0.03 g, 0.11 mmol) were combined in acetone (15 cm3, 99%) and heated to reflux under nitrogen for 22 hours. The solution was evaporated under reduced pressure, and the residue was taken up in dichloromethane (10 cm3) and water (10 cm3). The aqueous layer was extracted with dichloromethane (2×10 cm3), and the combined extracts were washed with water (2×20 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was chromatographed (SiO2, dichloromethane) to give the phenol, (0.02 g, 15%), as a white solid, mp 63-69° C.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])=[O:46]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])=[O:46])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccccc1Cl
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(2-chlorophenyl)ethanone and isolated as yellow gum. MS(m/e): 435.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCCCC1c1cccc(O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cccc(C2CCCCNC2=O)c1

Procedure:
A suspension of hexahydro-3-(3-hydroxyphenyl)-2H-azepin-2-one (4.1 g), anhydrous potassium carbonate (5.6 g) and dimethyl sulphate (2.52 g) was heated under reflux with stirring in acetone (50 ml). After cooling the solution was filtered and evaporated to dryness under reduced pressure. The product was recrystallised from diisopropyl ether/ethyl acetate affording the title compound, identical to that obtained by the method of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>C(OCC)(=O)C.C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[O:14][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COP(=O)(OC)C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COP(=O)(OC)C(O[Si](C)(C)C(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a mixture of 3.48 g of product from Example 97 and 12 ml of dimethylformamide is added 1.86 g of t-butyldimethylsilyl chloride and 1.86 g of imidazole. After stirring the reaction at room temperature for 2 hours, the mixture is diluted with 50% ethyl acetate/diethyl ether, washed 5 times with water, once with saturated sodium bicarbonate and once with saturated sodium chloride. The organic layer is dried, filtered and concentrated in vacuo to give 3.90 g of the desired silylated product.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=C(OC)C=1)(C)(C)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:49])[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[NH:26][C:25]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:38][C:37]=3[O:46][CH2:47]C)=[N:24]2)=[CH:19][CH:18]=1>>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([C:25]2[NH:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[C:23]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)([CH3:49])[N:24]=2)=[C:37]([O:46][CH3:47])[CH:38]=1)([CH3:43])([CH3:44])[CH3:45]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: COc1cc(C(C)(C)C)ccc1C(=O)Cl
Product: COc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-2-(4-tert-butyl-2-methoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 4-tert-butyl-2-methoxy-benzoyl chloride (prepared from 4-tert-butyl-2-hydroxy-benzoic acid) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [CH3:1][C:2]([O:7]/[N:8]=[C:9](\[C:16]([NH:18][C@@H:19]1[C:22](=[O:23])[N:21]2[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][S:27][C@H:20]12)=[O:17])/[C:10]1[N:14]=[C:13]([NH2:15])[S:12][CH:11]=1)([C:4]([OH:6])=[O:5])[CH3:3].P(=O)(O)(O)[OH:39]>>[CH3:3][C:2]([O:7]/[N:8]=[C:9](/[C:16]([NH:18][C@@H:19]1[C:22](=[O:23])[N:21]2[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][S:27][C@H:20]12)=[O:17])\[C:10]1[N:14]=[C:13]([NH2:15])[S:12][CH:11]=1)([C:4]([OH:6])=[O:5])[CH3:1].[OH2:39].[OH2:5].[OH2:5].[OH2:5].[OH2:5]
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Reactant: O=P(O)(O)O
Product: CC(C)(O/N=C(/C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Product: O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
The pH of the ceftazidime solution was lowered to 4.5 with 4M phosphoric acid, and the solution was seeded. The solution was stirred for 21/2 hr at 0-5° C., during which the pH had risen to 4.7 and a large amount of crystals had formed. Phosphoric acid (4M) was then added dropwise over a 1 hr period to achieve a pH of 3.7. More acid was added dropwise over the next 1/2 hr to maintain this pH. After the pH was stabilized, the slurry was stirred slowly in an ice bath for 1 hr. The crystals were filtered and washed twice with cold deionized water (2×30 mL) and then with cold acetone (30 mL). The product was dried overnight at ambient temperature at a pressure of about 80 mm Hg. This procedure gave 13.57 g of ceftazidime pentahydrate. The assay was 85.4%, and the corrected yield was 77.3%. Another 11.1% yield was obtained from the combined mother liquors and washes.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S=C1NC(CCC2NC3=NC=C(C4C=CC([S:50]([NH:53][C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=5[CH3:60])(=[O:52])=[O:51])=CC=4)C=C3N=2)CCCC1.N>CO>[NH2:25][C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:14]2[NH:13][C:10]3=[N:11][CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([S:50]([NH:53][C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=5[CH3:60])(=[O:51])=[O:52])=[CH:5][CH:6]=4)[CH:8]=[C:9]3[N:15]=2)[N:24]=1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Agent: N
Solvent: CO
Product: Cc1ccccc1NS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(N)=N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 71 mg of 4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide (compound A9) and 3.2 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 66 hours. Subsequently, the solution is concentrated in vacuo to yield 60 mg of the pure title compound as an amorphous, colorless solid of m.p. 215° C. ESI-MS: 503.4 (MH+), TLC: Rf=0.25 (HPTLC RP-C18; acetonitrile/water 2:1 parts by volume).
Reaction SMILES: O1C2C(=CC=CC=2)[C@H:4]([NH:11]C([C@@H]2CC3C(=CC([C@H]4C[C@@H](C(=O)N[C@H]5C6C(=CC=CC=6)CCC5)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C4)=CC=3)CN2C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O[C:75]([N:77](C)[C@@H:78]([CH3:152])[C:79]([NH:81][C@@H:82]([C:148]([CH3:151])([CH3:150])[CH3:149])[C:83]([N:85]1[CH2:89][C@@H:88]([C:90]2[CH:99]=[C:98]3[C:93]([CH2:94][C@@H:95]([C:121](=[O:133])[NH:122][C@H:123]4[C:132]5[C:127](=[CH:128][CH:129]=[CH:130][CH:131]=5)[CH2:126][CH2:125][CH2:124]4)[N:96]([C:100](=[O:120])[C@@H:101]([NH:106][C:107](=[O:119])[C@@H:108]([N:110](C(OC(C)(C)C)=O)[CH3:111])[CH3:109])[C:102]([CH3:105])([CH3:104])[CH3:103])[CH2:97]3)=[CH:92][CH:91]=2)[CH2:87][C@H:86]1[C:134]([NH:136][C@@H:137]([CH2:141][C:142]1[CH:147]=[CH:146][CH:145]=[CH:144][CH:143]=1)[C:138](O)=[O:139])=[O:135])=[O:84])=[O:80])=O)(C)(C)C.CC1OC([C@@H](N)CC2C=CC=CC=2)=NC=1.C(O)(C(F)(F)F)=O>>[CH3:104][C:102]([CH3:103])([CH3:105])[C@H:101]([NH:106][C:107](=[O:119])[C@@H:108]([NH:110][CH3:111])[CH3:109])[C:100]([N:96]1[C@H:95]([C:121]([NH:122][C@H:123]2[C:132]3[C:127](=[CH:128][CH:129]=[CH:130][CH:131]=3)[CH2:126][CH2:125][CH2:124]2)=[O:133])[CH2:94][C:93]2[C:98](=[CH:99][C:90]([C@H:88]3[CH2:87][C@@H:86]([C:134](=[O:135])[NH:136][C@H:137]([C:138]4[O:139][C:3]([CH3:2])=[CH:4][N:11]=4)[CH2:141][C:142]4[CH:143]=[CH:144][CH:145]=[CH:146][CH:147]=4)[N:85]([C:83](=[O:84])[C@@H:82]([NH:81][C:79](=[O:80])[C@@H:78]([NH:77][CH3:75])[CH3:152])[C:148]([CH3:149])([CH3:151])[CH3:150])[CH2:89]3)=[CH:91][CH:92]=2)[CH2:97]1)=[O:120]
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCOc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: Cc1cnc([C@@H](N)Cc2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)c1ncc(C)o1)C(C)(C)C
Yield: 40 %

Procedure:
Following procedures analogous to those for the preparation of Compounds F and G of Example 46, (S)-2-((2S,4R)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidine-2-carboxamido)-3-phenylpropanoic acid (Compound D of Example 46, 45 mg, 0.044 mmol) and (S)-1-(5-methyloxazol-2-yl)-2-phenylethanamine, TFA (15 mg, 0.049 mmol) were converted to the title compound (19 mg, 40% over 2 steps). MS (ESI+) m/z 1001.1 (M+H)+.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14]>CN1C(=O)N(C)CCC1>[CH:1]1([O:7][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CBr)OC
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COC(COC1CCCCC1)OC
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Cyclohexanol (11.00 g) was added slowly over 2 hours to a stirred suspension of sodium hydride (4.80 g, 50% w/w dispersion in oil) in dry DMPU (100 ml) at 50° C. under argon. The mixture was stirred for an additional 30 minutes, then cooled to 5° C. and treated with 2-bromo-1,1-dimethoxyethane (16.9 g). Stirring was continued for 18 hours at ambient temperature. The mixture was then poured into ice-water (250 ml). The aqueous mixture was extracted with ether (4×100 ml). The combined extracts were washed successively with water (3×100 ml) and saturated brine (100 ml), then dried (MgSO4) and evaporated. Flash chromatography of the residue, eluting successively with hexane, 5% v/v ethyl acetate hexane and 10% v/v ethyl acetate/hexane, gave 2-cyclohexyloxy-1,1-dimethoxyethane as an oil (A) (7.32 g). This was used without further purification.
Reaction SMILES: Br[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:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][OH:29])=[CH:18][CH:17]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]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:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][OH:29])=[CH:18][CH:17]=1
Reactant: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCC2CO)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(-c3ccco3)cc2C1=CNc1ccc(CN2CCCC2CO)cc1
Temperature: 100 °C
Yield: 59 %

Procedure:
6-Bromo-4-{[4-(2-hydroxymethyl-pyrrolidin-1-ylmethyl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (130 mg, 0.26 mmol) and 2-furyltributyltin (270 mg, 0.76 mmol) and PdCl2(PPh3)2 (30 mg) is mixed in N,N-dimethylformamide (4 mL) and degassed. The solution resulted is heated at 100° C. for 1 hour. After the mixture cooled to room temperature, the N,N-dimethylformamide is removed and the residue is purified through chromatography to afford the title compound (68 mg, 59%). MS (ESI): 444.1 (M+1)+1.
Reaction SMILES: C(OC(=O)C([NH:16][C:17](=[O:32])[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:20][CH:19]=1)CC1C=CC(C#N)=C(F)C=1)C.CCN=C=NCCCN(C)C.[C:45]([O:49][C:50]([NH:52][C:53]1[CH:61]=[CH:60][C:56]([C:57]([OH:59])=O)=[CH:55][CH:54]=1)=[O:51])([CH3:48])([CH3:47])[CH3:46].C([O:64][C:65](=[O:78])[CH:66]([NH2:77])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]#[N:75])=[C:70]([F:76])[CH:69]=1)C>C(Cl)Cl>[C:45]([O:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][C:56]([C:57]([NH:77][CH:66]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([C:74]3[N:16]=[C:17]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:22][CH:23]=4)[O:32][N:75]=3)=[C:70]([F:76])[CH:69]=2)[C:65]([OH:78])=[O:64])=[O:59])=[CH:60][CH:61]=1)=[O:51])([CH3:46])([CH3:47])[CH3:48]
Reactant: CCOC(=O)C(Cc1ccc(C#N)c(F)c1)NC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C(N)Cc1ccc(C#N)c(F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)NC(Cc2ccc(-c3noc(-c4ccc(NC(=O)OC(C)(C)C)cc4)n3)c(F)c2)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
2-(4-tert-Butoxycarbonylamino-benzoylamino)-3-(4-cyano-3-fluoro-phenyl)-propionic acid ethyl ester. EDCI (560 mg, 2.92 mmol) was added to a solution of 4-tert-butoxycarbonylamino-benzoic acid (661 mg, 2.7 mmol) in dry CH2Cl2 (5 mL). After the mixture was stirred for 0.5 hr, 2-amino-3-(4-cyano-3-fluoro-phenyl)-propionic acid ethyl ester (627 mg, 2.66 mmol) was added and the mixture was stirred for another 5 hrs at room temperature. The mixture was partitioned between EtOAc and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound as a white solid (906 mg, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29])[CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1.Cl>[CH2:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:21]1[CH3:29])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in part A of Example 2, 14.3 g (0.05 mole) of tetrachlorophthalic anhydride, 16.0 g (0.07 mole) of 76 percent active 1-n-butyl-2-methylindole and 13.3 g (0.10 mole) of aluminum chloride were interacted in 100 ml of benzene. The reaction mixture was drowned in 200 ml of five percent hydrochloric acid with stirring. The solid which formed was collected by filtration, washed with water and dried to obtain 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: Ro =R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =(CH2)3CH3), a pale yellow solid melting at 162°-164° C. The nuclear magnetic resonance spectrum was in accord with the structure.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([CH2:15][CH2:16][O:17][C:18]([N:20]1[C:29]2[C:24](=[N:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=2)[C@@H:23]([N:34]([CH2:41][C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=2)[C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[CH2:22][C@H:21]1[CH2:56][CH3:57])=[O:19])#[N:14].Cl>C1(C)C=CC=CC=1>[N:1]1[NH:2][N:3]=[N:14][C:13]=1[CH2:15][CH2:16][O:17][C:18]([N:20]1[C:29]2[C:24](=[N:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=2)[C@@H:23]([N:34]([CH2:41][C:42]2[CH:43]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=2)[C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[CH2:22][C@H:21]1[CH2:56][CH3:57])=[O:19]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCCC#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OCCc1nn[nH]n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
Add sodium azide (16 mg, 0.24 mmol) and triethylamine hydrochloride (33 mg, 0.24 mmol) to a solution of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid 2-cyano-ethyl ester (77 mg, 0.12 mmol) in toluene (2.4 mL). Stir the mixture at 80° C. for 1.5 h and at 100° C. overnight. Add more sodium azide (24 mg, 0.36 mmol) and triethylamine hydrochloride (50 mg, 0.36 mmol) and stir the mixture for 8 h at 100° C. Add more sodium azide (24 mg, 0.36 mmol) and triethylamine hydrochloride (50 mg, 0.36 mmol) and stir the mixture for 6 h at 100° C. Cool down to room temperature. Add 1 M HCl and extract the aqueous phase with dichloromethane. Wash the organic layers with water and brine, then dry over Na2SO4, filter, and concentrate. Purify the crude material by silica gel chromatography (elution with dichloromethane/methanol) to afford the title compound (55 mg, 66%). MS (ES+): 694 (M+H).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C[Mg]Cl.CON(C)C(C1CSC(=O)N1CC1C=CC(OC)=CC=1)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:1]([CH:4]1[CH2:8][S:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN2C(=O)SC[C@H]2C(C)=O)cc1
Agent: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Agent: C[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)SCC2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Preparation of (R)-4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one (A compound of Formula I): A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 0.805 L of a 3 M solution of methylmagnesium chloride in THF. The solution was purged with nitrogen and cooled to 0° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (250.0 g, 0.805 mol) was dissolved in 1.00 L of dry THF. The resulting solution was added to the solution of methyl magnesium chloride at a rate that maintained an internal reaction temperature less than 5° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 1.00 L of a 10% citric acid solution at a rate that maintained a temperature of less than 25° C. The mixture was diluted with 0.90 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 2.5 L of ethyl acetate. The organic phase was separated, concentrated to a final volume of ˜800 mL and cooled to room temperature. A suspension was formed by the addition of 16 L of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 170 g of 4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one was obtained (80% yield). 1H NMR (300 MHz, DMSO) δ 7.14 (d, 8.9 Hz, 2H), 6.88 (d, 8.9 Hz, 2H), 4.48 (dd, J=9.4, 2.6 Hz, 1H), 4.27 (AB, JAB=15.2 Hz, ΔνAB=267.3 Hz, 2H), 3.72 (s, 3H), 3.62 (dd, J=11.9, 10.0 Hz, 1H), 3.37 (dd, J=11.8, 2.6 Hz, 1H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO) δ 26.9, 27.9, 47.2, 55.8, 66.0, 114.7, 129.1, 130.0, 159.4, 171.7, 205.1; [α]26.5D-56.0° (c=1.39, EtOH).
Reaction SMILES: [CH2:1]([Li])CCC.C([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:11]12[CH3:12])[C:24]1[CH:23]=[CH:22][C:21]([OH:28])=[CH:20][C:19]=1[CH2:18][C@H:17]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C(O)=O)(=O)C.[C:42]([CH:45]([CH:47]([C:49]([O-:51])=O)O)O)(O)=O.[Na+]>C(OCC)C.O1CCCC1>[OH:28][C:21]1[CH:22]=[CH:23][C:24]2[C@@H:25]3[C@H:16]([C@H:13]4[C@@:11]([CH2:27][CH2:26]3)([CH3:12])[C@@H:10]([OH:9])[CH2:15][CH2:14]4)[C@H:17]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:49](=[O:51])[CH2:47][CH2:45][CH2:42][CH3:1])[CH2:18][C:19]=2[CH:20]=1
Reactant: [Li]CCCC
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCCCCCCC(=O)O)Cc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: O=C([O-])C(O)C(O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC(=O)CCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 2 h

Procedure:
n-Butyl-lithium (0.27 ml. of a 1.5 molar solution in diethyl ether) was added to a stirred solution of 11-(17β-acetoxy-3-hydroxyoestra-1,3,5(10)-trien-7α-yl)undecanoic acid (Example 2; 0.046 g.) in tetrahydrofuran (1 ml.) and the mixture was stirred at laboratory temperature for 2 hours. Saturated aqueous sodium hydrogen tartrate solution (2 ml.) was added and the mixture was extracted three times with ethyl acetate (5 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 17:3 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 15-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)pentadecan-5-one, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.