Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2([C:9]([CH3:12])([CH3:10])[CH3:11])[O:14][CH2:4]2)=[CH:16][CH:17]=1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)C(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)C1(c2ccc(Cl)cc2)CO1
Temperature: 50 °C
Yield: 95 %

Procedure:
A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyl oxosulphonium iodide (0.03 mol) in dry dimethyl sulphoxide (40 ml). A solution of 4-chlorophenyl tertiary butyl ketone (0.025 mol) in dry dimethyl sulphoxide (10 ml) was added dropwise at room temperature and the solution heated at 50° C. for 2.5 hours. After cooling to room temperature the solution was extracted with ether (150 ml), washed with water and dried over anhydrous sodium sulphate. Removal of the solvent gave 1-(4-chlorophenyl)-1-t-butyl-ethylene oxide (95%) as a colourless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5](Br)[C:6](=O)[CH2:7][CH2:8][CH3:9])[CH3:2].C(N(CC)CC)C.[NH2:20][C:21]([NH2:23])=[S:22]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[S:22][C:21]([NH2:23])=[N:20][C:6]=1[CH2:7][CH2:8][CH3:9])=[O:12])[CH3:2]
Reactant: CCCC(=O)C(Br)C(=O)OCC
Reactant: NC(N)=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCc1nc(N)sc1C(=O)OCC
Reaction time: 16 h
Yield: 33.6 %

Procedure:
2-Bromo-3-oxo-hexanoic acid ethyl ester (5.9 g, 25 mmol), was dissolved in 60 mL of ethanol containing triethylamine (4.2 mL, 30 mmol) and thiourea (1.9 g, 25 mmol). The colorless solution was protected from light and allowed to stir for 16 hours. The resulting red suspension was evaporated to dryness and dissolved in a minimum of dichloromethane. This solution was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The organic layer was separated and filtered to remove a fine red precipitate which remained suspended in the organic phase. The solvent was removed and then the solid was dissolved in a minimum of 50/50 (v/v) ethyl acetate and 1 N aqueous solution of hydrochloric acid. The layers were separated and the aqueous layer was washed with an equal volume of ethyl acetate. After discarding the organic layers, the aqueous layer was then placed in an ice bath with an equal volume of ethyl acetate. Sodium hydroxide (1N) was then slowly added with vigorous swirling until the aqueous phase was basic. The layers were separated and the aqueous layer was washed two additional times with ethyl acetate. The combined organic layers were washed three times with an equal volume of a solution of saturated aqueous sodium bicarbonate followed by a solution of saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness to yield a pale yellow solid (1.8 g, 8.4 mmol, 34%) ESI-MS m/z calc. 214.1. found 215.3 (M+1)+ Retention time 1.90 minutes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1C(C)C([O-])=O.[Na+].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:36])[CH:32](Br)[CH2:33][CH3:34])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[C:13]1[C:21]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:36])[CH:32]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:33][CH3:34])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24]
Reactant: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Reactant: CC(C(=O)[O-])c1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium 2-(2-thiazolyl)propionate (148 mg) is introduced into DMF (5 ml), and 2-(1-benzothien-2-yl)-5-[(2-bromobutanoyl)amino]benzamide (Example 8A; 171 mg), HATU (291 mg) and 4-methylmorpholine (194 mg) are added. The reaction mixture is stirred at RT overnight. The reaction mixture is concentrated and the residue is purified by preparative HPLC. 101 mg (36% of theory) of product are isolated.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH2:20])=[N:16][NH:17]2)=[CH:13][CH:12]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH:20][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])=[N:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)c1ccccn1
Temperature: 8 °C
Reaction time: 18 h

Procedure:
4.2 cm3 of diisopropylethylamine are added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine. The reaction medium is cooled to about 8° C. to add 1.08 g of picolinoyl chloride hydrochloride, and the temperature is allowed to return to room temperature over 18 hours. The reaction medium is concentrated to dryness under reduced pressure (2 kPa; 40° C.) and the residue is then taken up in 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of water and then with 25 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtration and concentration under reduced pressure (2 kPa; 40° C.), the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 2×15 cm of diisopropyl ether. After filtration on a sinter funnel and drying under reduced pressure (90 Pa; 50° C.), 572 mg of N-[6-chloro-1H-indazol-3-yl]-2-pyridinecarboxamide are obtained in the form of a white solid melting at 177° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([Cl:21])=[N:13][C:14]2[N:15]([N:18]=[CH:19][CH:20]=2)[C:16]=1Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][O:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>C(O)(C)C>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([Cl:21])=[N:13][C:14]2[N:15]([N:18]=[CH:19][CH:20]=2)[C:16]=1[NH:40][C:37]1[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:39][CH:38]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCCOc1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1c(Cl)nc2ccnn2c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COCCOc1ccc(Nc2c(CCO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Temperature: 85 °C

Procedure:
To an isopropanol (3.0 mL) solution containing 6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5,7-dichloropyrazolo[1,5-a]pyrimidine (512 mg, 1.49 mmol), triethylamine (836 μL, 5.96 mmol) and 4-(2-methoxyethoxy)phenylamine (299 mg, 1.79 mmol) were added, and this mixture was heated at 85° C. with stirring. After the reaction, the solvent was concentrated, sodium hydrogen carbonate was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[C@H:18]([C:19]([OH:21])=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.C(N(CC)CC)C>[C:1]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[C@H:18]([C:19]([O:21][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)OCOC(=O)C(C)(C)C
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere, to the solution of 3.4 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid in 11 ml of dry N,N-dimethylformamide, 1.4 ml of triethylamine and 1.5 g of chloromethyl pivalate are added, and stirred at 90° C. for 6 hours. The reaction mixture is poured into 100 ml of ice-water, and extracted with ether. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.8 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 4.1 g (91%), mp. 69°-69.5° C. (benzene-n-hexane), [α]D25 -153.8° (c=1.0, methanol).
Reaction SMILES: C(OC(C)(C)C)(=O)[NH:2][NH2:3].[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])=[C:13]([F:24])[CH:12]=1>CN(C)C1C=CN=CC=1.C(#N)C>[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([NH:2][NH2:3])=[O:18])=[C:13]([F:24])[CH:12]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1F)C(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(Oc1ccc(Cl)cc1F)C(=O)NN
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.6 %

Procedure:
WSC•monohydrochloride (18.1 g), tert-butyl carbazate (10.5 g) and 4-(dimethylamino)pyridine (461 mg) were sequentially added to a solution of 2-(4-chloro-2-fluorophenoxy)-2-methylpropanoic acid (17.6 g) in acetonitrile (170 ml), followed by stirring at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and ethyl acetate was then added thereto. The organic layer was washed with water, 0.5M hydrochloric acid, saturated aqueous sodium bicarbonate solution-water (1:1) and then saturated brine in this order and was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting oil (21.8 g) was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate was added thereto, followed by stirring at room temperature for 5 hours and was then concentrated under reduced pressure. Ethyl acetate was added thereto, followed by stirring and the solid was thus separated by filtration. Saturated aqueous sodium bicarbonate was added to the solid thus obtained, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine-water (1:1) and then saturated brine in this order and was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain, as a colorless oil, 2-(4-chloro-2-fluorophenoxy)-2-methylpropanohydrazide (12.8 g).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[NH4+].[CH2:6]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH3:7]>S(=O)(=O)(O)O>[CH2:6]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2])[CH3:7]
Reactant: CCc1ccc(N)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCc1ccc(N)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Ammonium nitrate (39.6 g, 0.49 mol) is added portionwise to a chilled (ice-bath) solution of 4-ethylaniline (20 g, 0.16 mol) in concentrated sulfuric acid (100 ml, maintaining the temperature −10° to 0° C. by external cooling. The reaction mixture is stirred for two hours, then poured onto crushed ice, and the precipitate is collected by filtration. The solid is taken up in water, the solution made neutral by addition of dilute aqueous sodium hydroxide solution and the extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo to give 4-ethyl-3-nitroaniline (20 g).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.[BrH:22]>C(O)C>[BrH:22].[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[N:9]1[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: Br
Solvent: CCO
Product: c1ccc2[nH]c(N3CCCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (5.22 g, 18.1 mmol) and aqueous 48% hydrobromic acid solution (25 mL). Heat to reflux. After 4 hours, cool to ambient temperature and concentrate in vacuo to give a residue. Combine the residue and ethanol (150 mL). Evaporate in vacuo to a volume of about 75 mL and cool to give a solid. Collect solid by filtration, rinse with ethanol and then diethyl ether, and dry in vacuo to give 4-(1H-benzimidazol-2-yl)[1,4 ]diazepane hydrobromic acid salt. Elemental Analysis calculated for C12H16N4•2HBr: C, 38.12; H, 4.80; N, 14.82. Found: C, 38.17; H, 4.84; N, 14.60.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.Cl.[F:37][C:38]1([F:42])[CH2:41][NH:40][CH2:39]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[F:37][C:38]1([F:42])[CH2:41][N:40]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=2)[CH2:39]1
Reactant: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)nc1
Reactant: FC1(F)CNC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Product: Cc1ccc(COc2ccc3nc([C@@H]4CCCC[C@@H]4C(=O)O)n(Cc4ccc(N5CC(F)(F)C5)cc4)c3c2)nc1

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting (1R*,2S*)-2-(1-(4-bromobenzyl)-6-((5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid, 3,3-difluoroazetidine hydrochloride (4 eq), and 5 eq LiHMDS. MS (ESI): mass calcd. for C31H32F2N4O3, 546.24; m/z found, 547.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.51 (s, 1H), 6.82 (d, J=7.9, 1H), 6.73 (d, J=8.8, 1H), 6.61 (d, J=7.9, 1H), 6.23-6.03 (m, 4H), 5.68 (d, J=8.4, 2H), 4.57 (q, J=16.7, 2H), 4.29 (s, 2H), 3.36 (t, J=11.9, 4H), 2.80-2.70 (m, 1H), 2.10-2.00 (m, 1H), 1.61-1.46 (m, 4H), 1.21-1.13 (m, 1H), 1.12-0.86 (m, 4H), 0.75-0.55 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][O:14][CH3:15]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)c1ccc(O)cn1
Yield: 52 %

Procedure:
Following the same procedure as described in example 41, step A, 5-hydroxypicolinic acid (6.2 g, 1.0 eq) was reacted with N,O-dimethylhydroxylamine hydrochloride (5.2 g, 1.2 eq) to get the desired product with column chromatography (4.25 g, 52% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[Cl:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[Cl:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(C)c(Cl)c2[nH]1
Product: CCOC(=O)c1cc2ccc(C)c(Cl)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 7-chloro-6-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:43][CH:44]([CH2:63][CH3:64])[C@@H:45]([C:47]1[O:48][C:49]([C:52]2[CH:57]=[CH:56][C:55]([O:58][C:59]([F:62])([F:61])[F:60])=[CH:54][CH:53]=2)=[N:50][N:51]=1)[OH:46].[F:65][C:66]([F:84])([CH2:81][CH2:82][CH3:83])[CH2:67][C@H:68]([NH:72][C:73]([N:75]1[CH2:80][CH2:79][O:78][CH2:77][CH2:76]1)=[O:74])[C:69](O)=[O:70]>C(Cl)Cl>[F:84][C:66]([F:65])([CH2:81][CH2:82][CH3:83])[CH2:67][C@H:68]([NH:72][C:73]([N:75]1[CH2:76][CH2:77][O:78][CH2:79][CH2:80]1)=[O:74])[C:69](=[O:70])[NH:43][C@H:44]([CH:45]([OH:46])[C:47]1[O:48][C:49]([C:52]2[CH:53]=[CH:54][C:55]([O:58][C:59]([F:61])([F:60])[F:62])=[CH:56][CH:57]=2)=[N:50][N:51]=1)[CH2:63][CH3:64]
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Reactant: CCC(N)[C@H](O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
PyBOP (68.69 mg, 0.13 mmol), diisopropylethylamine (0.023 mL, 0.13 mmol) and (S)-2-Amino-1-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-butan-1-ol (38.0 mg, 0.12 mmol) are added to a solution of (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (34 mg, 0.12 mmol) in dry methylene chloride (4 mL) and the reaction mixture is stirred overnight at room temperature. The reaction is quenched with aqueous NaHCO3, extracted twice with methylene chloride, the organic extracts are dried over Na2SO4 and evaporated under reduced pressure. Column chromatography on silica eluting with a mixture of methylene chloride and ethyl acetate gives morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-{hydroxy-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-methyl}-propylcarbamoyl)-hexyl]-amide as a solid (61 mg). LC/MS 71%, M+1=594
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C@H:27]([NH:29][CH2:30][C:31]([F:35])([CH3:34])[CH2:32][OH:33])[CH3:28])=[CH:18]1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[C@@H:8]1[C:18]2[NH:17][C:25]3[C:20]([C:19]=2[CH2:26][C@@H:27]([CH3:28])[N:29]1[CH2:30][C:31]([F:35])([CH3:34])[CH2:32][OH:33])=[CH:21][CH:22]=[CH:23][CH:24]=3
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(F)CO
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(F)CO)c(F)c1
Temperature: 90 °C
Yield: 10.3 %

Procedure:
(E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (565 mg, 2.50 mmol) was added to a suspension of 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-fluoro-2-methylpropan-1-ol (661 mg, 2.50 mmol) in toluene (11.3 ml)/acetic acid (1.25 ml). The reaction was heated to 90° C. for 5 h. After cooling, the volatiles were removed under vacuum, then the residue was passed through an SCX-2 column, eluting with methanol to remove unreacted aldehyde. The column was then eluted with NH3/MeOH to liberate the products. The basic filtrate was evaporated then the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (Isomer 1-122 mg, 10.3%) as a yellow solid and (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (Isomer 2-129 mg, 11% as a yellow/orange solid. Isomer 1-1H NMR (400 MHz, CDCl3, 27° C.) 1.10 (3H, d), 1.14 (3H, d), 2.54 (1H, dd), 2.62-2.73 (1H, m), 3.06-3.3 (2H, m), 3.40 (1H, dd), 3.56 (1H, t), 3.80 (3H, s), 3.87-4.08 (1H, m), 4.27 (1H, s), 5.16 (1H, s), 6.37 (1H, d), 7.01 (2H, d), 7.07-7.15 (2H, m), 7.14-7.24 (1H, m), 7.42-7.56 (2H min), 7.71 (1H, s). m/z (ES+), [M+H]+=473. Isomer 2—1H NMR (400 MHz, CDCl3, 27° C.) 1.15 (3H, d), 1.20 (3H, d), 2.65 (1H, dd), 2.79 (1H, t), 2.93-3.09 (2H, m) 3.57 (1H, dt), 3.70 (1H, dd), 3.78 (3H, s), 4.2-4.67 (1H, n), 5.42 (1H, s), 6.32 (1H, d), 6.94 (2H, d), 7.06-7.15 (2H, m), 7.19-7.27 (2H, n, 7.42 (1H, s), 7.51 (11H, dd), 8.02 (1H, s). m/z (ES+), [M+H]+=473.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([Li])CCC.CN([CH:27]=[O:28])C1C=CC=CC=1>CCOCC>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:27]=[O:28])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Brc1ccc(C2=CCCCC2)cc1
Reactant: CN(C=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(C2=CCCCC2)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7 g of p-(1-cyclohexenyl)-phenylbromide in 100 ml of absolute ether there is added at 5° C, while stirring and in an atmosphere of nitrogen, 50 ml of a solution of 4.3 g of n-butyl-lithium in absolute ether. The mixture is allowed to reach room temperature, stirred for 30 minutes at 30° C, then cooled to 20° C and a solution of 4 g of N-methyl-N-formyl-aniline in 50 ml of absolute ether is added dropwise, when the internal temperature rises to 30° C. After the reaction mixture has been allowed to continue to react for 30 minutes at room temperature, it is poured into 100 ml of ice cold 2N hydrochloric acid and extracted with ether. The ether layers are washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is distilled under a high vacuum and yields the p-(1-cyclohexenyl)-benzaldehyde having a boiling point of 110°-120° C (0.2 mm Hg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:4]=2[CH2:3]1.[Li+].[ClH:15].CN(C)CCCN=C=NCC.O.O[N:29]1[C:33]2C=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1>CN(C)C=O>[ClH:15].[NH2:29][C@@H:33]1[CH2:35][CH2:36][CH2:37][C@H:32]1[NH:31][C:11]([C:9]1[S:10][C:4]2[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=2[N:8]=1)=[O:13]
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3N)sc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.7 %

Procedure:
The compound (175 mg) obtained in Referential Example 61 was dissolved in N,N-dimethylformamide (3 ml), and to the solution lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (purity: 90%, 258 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (252 mg) and 1-hydroxybenzotriazole monohydrate (60 mg) were added. The mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure using a pump, and methylene chloride and a saturated solution of sodium hydrogencarbonate were added to the residue to separate an organic layer. The resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (methylene chloride:methanol=47:3). The resultant pale yellow oil was dissolved in a ethanol solution (5 ml) of hydrochloric acid, and the solution was stirred at room temperature for 1 hour. Ethyl acetate was then added, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue to collect precipitate formed by filtration, thereby obtaining the title compound (120 mg).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>C1COCC1>[O:22]=[C:20]([CH3:21])[CH2:19][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(=O)CCl
Reactant: O=C(O)c1cccc(S)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CSc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Mercapto-benzoic acid (5.0 g, 32.3 mmol) and triethylamine (11.3 mL, 81.1 mmol) were dissolved in THF at 0° C. Chloroacetone (2.7 mL, 33.9 mmol) was then added and the reaction was allowed to slowly warm to room temperature as it stirred overnight. Standard aqueous workup afforded the title compound which was brought forward to the next step without further purification.