Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39]C(C)(C)C)[N:34]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(O)=O>O>[O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([C:33]3[NH:34][C:35](=[O:39])[CH:36]=[CH:37][CH:38]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(OC(C)(C)C)n2)cc2cn[nH]c12
Solvent: O
Solvent: O=CO
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(=O)[nH]2)cc2cn[nH]c12
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Solid (±)-1-(6-tert-butoxypyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (previous example) (20.6 mg) was treated with 1 mL formic acid (90%). After 2 h, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water, saturated sodium bicarbonate solution, dried and concentrated. Further drying under high vacuum afforded the product (11.8 mg, 63.4%) as an off-white powder. MS (ESI) [M+H]+=527. HPLC tR=1.68 min.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:44]=N[C:46]([CH3:49])=[CH:47][CH:48]=1)[CH2:4][CH2:3]2.BrC1C=C[C:54]([S:57]C)=CN=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][C:46]([S:57][CH3:54])=[CH:49][N:44]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CSc1ccc(Br)nc1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(SC)cn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 5.9 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-bromo-5-(methylthio)pyridine (0.020 g, 0.100 mmol) was used in place of 3-bromo-6-methylpyridazine. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound as a white glassy solid (5.2 mg, 5.9% yield) bis TFA salt. LCMS: m/e 696.5 (M+H)+, 2.34 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.03 (d, J=1.8 Hz, 1H), 7.93-7.88 (m, J=8.2 Hz, 2H), 7.61-7.57 (m, 1H), 7.21-7.14 (m, J=8.2 Hz, 2H), 6.71 (d, J=8.9 Hz, 1H), 5.27 (dd, J=6.1, 1.5 Hz, 1H), 4.87 (s, 1H), 4.75 (br. s., 1H), 4.72 (br. s., 1H), 3.80-3.72 (m, 1H), 3.72-3.63 (m, 1H), 3.18-3.09 (m, 1H), 2.72-2.64 (m, 1H), 2.39 (s, 3H), 2.11 (dd, J=17.1, 6.4 Hz, 1H), 2.08-2.01 (m, 1H), 2.00-1.90 (m, 3H), 1.90-1.74 (m, 3H), 1.72 (s, 3H), 1.71-1.66 (m, 2H), 1.65-1.44 (m, 7H), 1.44-1.33 (m, 3H), 1.33-1.12 (m, 7H), 1.04 (s, 3H), 0.97 (s, 3H), 0.91 (br. s., 3H), 0.91 (br. s., 3H), 0.87 (s, 3H).
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([C:33]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][C:13]([O:12][CH:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]3)=[CH:21][CH:20]=4)=[O:23])[CH2:25][CH2:26]2)=[O:34])[CH2:32][CH2:31]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and cyclopropanoyl chloride. Light-yellow solid. MS (m/z): 439.5 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C@H:33]([C:40]([OH:42])=[O:41])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][C:8]([O:10][NH:32][C@H:33]([C:40]([OH:42])=[O:41])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1)=[O:9]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)ON[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
To a diclofenac solution (3 g, 10.13 mmoles) in tetrahydrofuan (50 ml) cooled at 0° C., 1,1′-carbonyldiimidazol (1.69 g, 10.13 mmoles) is added under stirring. After 10 minutes the solution is treated with (L) histidine (1.57 g, 10.13 mmoles) and left under stirring at room temperature for 4 hours. The reaction mixture is concentrated under vacuum, treated with methylene chloride and then washed in sequence with HCl 1% and then with water. The organic phase is anhydrified with sodium sulphate and evaporated under vacuum. The obtained residue is purified by chromatography on silica gel column, eluting with ethyl acetate. [2-[(2,6-dichlorophenyl)amino]benzeneacetyloxy](L)-histidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(O[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])(=O)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OCCOCOC(C)=O
Product: CC(=O)OCCOCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 138 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
2,6-Dichloropurine 5.5 g and 2-oxa-1,4-butanediol diacetate 513 g were placed in a flask and partially evacuated and then heated to 138° C., initially the mixture was too thick to stir but gradually gave rise to a melt which was stirred, and after 20 minutes was completely melted and the reaction mixture heated for 10 minutes more (total heat time = 30 minutes). The mixture was then cooled to room temperature and para-toluenesulphonic acid 150 mg was added, the vacuum reapplied and heating resumed with stirring. After 20 minutes heating vigorous bubbling was noted; the mixture was cooled to room temperature; chloroform was added, and the solution was extracted once with saturated aqueous sodium bicarbonate and once with water. The chloroform phase was dried over anhydrous sodium sulphate and evaporated. The residual oil was dissolved in benzene and applied to a column of 200 g. of silica gel in benzene. Benzene elution removed the acetate by-products. Ether elution gave 2,6-dichloro-9-(2-acetyloxyethoxymethyl)purine (64% yield). Recrystallization from benzene gave lustrous white flakes, m.p. 96°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([S:16]([CH3:17])=[O:31])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)O)cc1Cl
Reaction time: 5 h

Procedure:
In DCM (20 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio) pyrimidine-5-carboxylic acid (200 mg, 0.59 mmol). The solution was cooled in an ice bath and m-CPBA (101 mg, 0.59 mmol) was added. The reaction was conducted at ambient temperature for 5 h, followed by addition of water and extraction with DCM. The organic phase was dried and concentrated to give a solid which was used in the subsequent procedure without further purification.
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:15]=[C:14]([F:16])[C:13]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][C:10]=1[NH2:11].[N-:28]=[N+:29]=[N-].[Na+]>FC(F)(F)C(O)=O>[Cl:8][C:9]1[CH:15]=[C:14]([F:16])[C:13]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][N:18]=2)=[CH:12][C:10]=1[N:11]=[N+:28]=[N-:29]
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
With ice-cooling, initially 9.5 g (92 mmol) of tert-butyl nitrite were added dropwise to a solution of 20 g (62 mmol) of 2-chloro-5-(3-chloro-5-trifluoromethyl-2-pyridyl)-4-fluoroaniline in 40 ml of trifluoroacetic acid, and—with strong evolution of gas—6 g (92 mmol) of sodium azide were then added a little at a time. The mixture was stirred for 16 hours, and a further 15 ml of trifluoroacetic acid and 1.7 g (17 mmol) of tert-butyl nitrite were then added to the reaction mixture. Stirring was subsequently continued for another 30 minutes, and the mixture was then poured onto 0.3 l of ice-water. The resulting solid fraction was separated off and washed with 50 ml of water. For purification, the crude product was initially dissolved in 100 ml of toluene. The resulting toluene phase was then washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and finally concentrated. Yield: 90%;
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Product: Fc1cc(CNc2nccc(-n3cnc4ccccc43)n2)cc(C(F)(F)F)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-fluoro-5-trifluoromethylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 388.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (s, 1H); 8.46 (d, J=5.4 Hz, 1H); 7.99 (br s, 1H); 7.86 (d, J=8.7 Hz, 1H); 7.49 (s, 1H); 6.90 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.82 (d, J=6.2 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[C:9](=O)[C:8](Cl)=[C:7](Cl)[C:5](=O)[C:4]=1[C:13]#N)#N.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:1]1[C:8]2[CH:9]=[CH:3][C:4]3=[C:5]4[C:13]=2[C:4]2[C:5]5[C:16]6[C:17]4=[C:18]([CH:19]=[CH:20][C:15]=6[CH2:21][C:7]=5[CH:8]=[CH:9][C:3]1=2)[CH2:13]3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccccc1
Product: c1cc2c3c4c1Cc1ccc5c(c14)c1c(ccc(c31)C2)C5
Temperature: 110 °C
Yield: 67 %

Procedure:
First, a double-necked flask of 10 mL was subjected to vacuum and dried by heat, and subsequently, its volume was displaced with argon. Next, a solution obtained by solving hexahydrosumanene (0.0 11 mmol, 3 mg) into 2 mL of toluene was added into the flask by using a syringe, and DDQ (0.0385 mmol, 9 mg) further was added therein, and subsequently, the system was heated at 110° C. for 20 hours. After the reaction, the solvent was evaporated under a reduced pressure, and residues were separated by thin layer chromatography (hexane), thereby obtaining Sumanene (yield: 2 mg, isolation yield: 67%) as an objective compound. Physical properties of this compound will be described below. In addition, UV-VIS absorption spectrograms of this compound will be shown in FIGS. 1 to 5. Used solvents are cyclohexylamine (CHA) in FIG. 1, tetrahydrofuran (THF) in FIG. 2, acetonitrile (CH3CN) in FIG. 3 and dichloromethane (CH2Cl2) in FIG. 4, where concentrations of all the solutions are 1.0×10−4 M. Moreover, FIG. 5 is a view showing all of the spectrograms of FIGS. 1 to 4 in one.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]3[C:9](=[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]=3[OH:28])[S:18][N:19]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccc(F)cc3)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2snc(-c3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(4-Fluoro-phenyl)-4-hydroxy-7-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 422.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([NH:17][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-methyl-3 nitrobenzoyl chloride (20 g) in methylene chloride (200 mL) at 0° C. was added a mixture of cyclopropylamine (7.62 mL) and triethylamine (28 mL). The mixture was allowed to warm to room temperature and stirred for a further 16 hours. The reaction mixture was evaporated in vacuo and a saturated aqueous solution of sodium bicarbonate was added. The precipitated solid was filtered off and washed with isohexane and dried (magnesium sulphate) to give N-cyclopropyl-4-methyl-3-nitrobenzamide as a colourless solid (22.9 g); NMR Spectrum: (DMSOd6) 0.60 (m, 2H), 0.72 (m, 2H), 2.56 (s, 3H), 2.87 (m, 1H), 7.60 (d, 1H), 8.06 (m, 1H), 8.41 (d, 1H), 8.67 (d, 1H); Mass Spectrum: M+H+ 221. B) A suspension of N-cyclopropyl-4-methyl-3-nitrobenzamide (22.92 g) and 10% palladium on carbon (2 g) in absolute alcohol (500 mL) was agitated under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate evaporated to dryness to give the title compound as a colourless solid (17.1 g); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.65 (m, 2H), 2.07 (s, 3H), 2.80 (m, 1H), 6.92 (m, 2H), 7.06 (d, 1H), 8.09 (d, 1H); Mass Spectrum: M+H+ 191.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.Cl.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:31].[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[S:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:29])[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:26][CH:27]=2)=[CH:19][CH:20]=1
Reactant: Cc1csc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc2nc(SCc3ccc(C(=O)c4ccc(OCCN5CCCCC5)cc4)cc3)n(C)c(=O)c12
Yield: 77.9 %

Procedure:
A solution of 3,5-dimethyl-2-[4-(4-hydroxybenzoyl)benzylthio]thieno[2,3-d]pyrimidin-4(3H)-one (255 mg), 1-(2-chloroethyl)piperidine hydrochloride (122 mg) and potassium carbonate (250 mg) in DMF (8 ml) was stirred at 60° C. for 15 hours. This reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water and dried. Then, HCl/ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (268 mg).
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[CH2:9]([OH:11])[CH3:10].[C:12]1([CH2:22][C:23]([OH:25])=O)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O>O>[CH2:9]([O:11][C:19]([CH:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][C:23]1=[O:25])=[O:21])[CH3:10]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1C(=O)Cc2ccccc21

Procedure:
To a stirred mixture of sodium hydride (126 g. of a 57% suspension in nujol), 2000 ml. of benzene and 2 ml. of ethanol heated at its reflux temperature under dry nitrogen is added dropwise the diethyl ester of o-phenylene-diacetic acid (335.6 g.) in 700 ml. of benzene. The mixture is refluxed 1.5 hours, poured into water and extracted with ether. The ether extracts are dried and concentrated to give an oil which is crystallized from ethanol-water to give 220 g. of the title product withm m.p. 58°-61°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:12]([C:14]1([NH:17][C:18]([C@@H:20]2[CH2:24][C@@H:23]([S:25]([C:28]3[CH:33]=[CH:32][C:31](F)=[CH:30][C:29]=3[C:35]([F:38])([F:37])[F:36])(=[O:27])=[O:26])[CH2:22][N:21]2[C:39]2[N:40]([CH:45]3[CH2:48][CH2:47][CH2:46]3)[N:41]=[C:42]([CH3:44])[CH:43]=2)=[O:19])[CH2:16][CH2:15]1)#[N:13].C(OC(C)=O)(C)C>CC(N(C)C)=O>[C:12]([C:14]1([NH:17][C:18]([C@@H:20]2[CH2:24][C@@H:23]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:30][C:29]=3[C:35]([F:36])([F:38])[F:37])(=[O:26])=[O:27])[CH2:22][N:21]2[C:39]2[N:40]([CH:45]3[CH2:48][CH2:47][CH2:46]3)[N:41]=[C:42]([CH3:44])[CH:43]=2)=[O:19])[CH2:16][CH2:15]1)#[N:13]
Reactant: c1cn[nH]c1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)OC(C)C
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(-n4cccn4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Yield: 20 %

Procedure:
Pyrazole (5 mg, 67 umol; CAS Reg. No. 288-11-9) and cesium carbonate (18 mg, 56 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (30 mg, 56 umol; example 388 g) in DMA (0.9 ml) under an argon atmosphere. The mixture was heated for 48 h to 90° C. and for additional 4 h to 120° C. in a shaking reactor. Ice water/brine 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give a brown oil which was purified by preparative HPLC to give the title compound (6.5 mg, 11 umol; 20%) as colorless oil. MS (ESI): m/z=588.4 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:11](Cl)=[O:12].[CH2:18]([O:20][C:21]([C@:23]1([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:28]([NH2:29])[CH2:27][C@@H:26]2[C@H:24]1[C@@:25]2([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:18]([O:20][C:21]([C@:23]1([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:28]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:8]([Cl:7])[CH:9]=2)[CH2:27][C@@H:26]2[C@H:24]1[C@@:25]2([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NC(=O)c3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
7.3 μL of pyridine and 14 mg of 3,4-dichlorobenzoyl chloride were added to 17 mg of (1R,2R,3R,5R,6R)-3-amino-2-t-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.17 mL of chloroform, and the mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: chloroform-ethanol=100:1), thereby yielding 21 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzoylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [NH:1]([C:8]([C:10]1[N:11]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:1]([C:8]([C:10]1[N:11]([CH2:27][C:28]([OH:30])=[O:29])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:14][CH:13]=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CC(=O)O

Procedure:
70 mg (0.15 mmol) of tert-butyl {2-(anilinecarbonyl)-5-[(3,3-dimethylbutanoyl)-amino]-1H-indol-1-yl}acetate from Example LIII, 0.50 ml of trifluoroacetic acid and 1 ml of dichloromethane are stirred together at RT for one hour. The solvent is removed under reduced pressure and the residue is dried in vacuo.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](C)=[N:20][C:21](O)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:26])=[O:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:41]([Cl:43])Cl>>[Cl:43][CH2:41][C:21]1[N:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:26])([CH3:27])[N:5]([C:3](=[O:4])[CH:2]([F:28])[F:1])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: Cc1nc(O)ccc1-c1ccc([C@H]2OC(C)(C)N(C(=O)C(F)F)[C@@H]2CF)cc1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CCl)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-5-[4-(6-hydroxy-methyl-pyridin-3-yl)-phenyl]-2,2-dimethyl-oxazolidin-3-yl}-ethanone (1660 mg, 4.2 mmol) and triethylamine (0.88 ml, 6.31 mmol) in CH2Cl2 (30 ml) is treated with methanesulfonyl chloride (0.49 ml, 6.31 mmol) and stirred at ambient temperature for 16 hours. The reaction mixture is concentrated to dryness to afford the title compound as a red oil (1.53 g): 1H NMR (400 MHz, CDCl3) 1.60-1.77 (m, 6H), 4.53-4.84 (m, 5H), 5.25-5.31 (m, 1H), 6.12 (t, 1H), 7.58 (d, 2H), 7.65 (d, 2H), 7.68 (d, 1H), 8.03-8.07 (m, 1H), 8.86-8.90 (m, 1H). m/z M+H 413.