Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[C:12]([NH:15][NH2:16])(=[O:14])[CH3:13].CN1CCOCC1.CN(C)CCCN=C=NCC.[F:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[C:51](O)=[O:52])(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl>[C:12]([NH:15][NH:16][C:51]([C@@H:46]1[CH2:47][CH2:48][CH2:49][CH2:50][N:45]1[S:42]([C:39]1[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=1)(=[O:44])=[O:43])=[O:52])(=[O:14])[CH3:13]
Reactant: CC(=O)NN
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(=O)NNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
1-Hydroxybenzotriazole hydrate (162 mg), acethydrazide (81 mg), N-methylmorpholine (275 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (230 mg) were added to a stirred solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38] (287 mg) in dichloromethane (3 ml). The reaction mixture was stirred for 3 hours after which time the mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford N′2-acetyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarbohydrazide (340 mg) as a white solid.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=1[CH3:20].[B:21](OC)([O:24]C)[O:22]C>C(OCC)C>[CH3:20][C:13]1[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:12]=1[B:21]([OH:24])[OH:22]
Reactant: COB(OC)OC
Reactant: CSc1ccc(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CSc1ccc(B(O)O)c(C)c1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 50 %

Procedure:
1.7M tert-Butyllithium in pentane (6.70 mL, 11.39 mmol) was added dropwise to a solution of 1-bromo-2-methyl-4-(methylthio)benzene (1.2 g, 5.53 mmol) in diethyl ether (120 mL) at −78° C. over 15 min. The mixture was stirred at −78° C. for 2 min, then charged with trimethyl borate (0.661 mL, 5.91 mmol) dropwise over 2 min at −78° C., stirred at −78° C. for 15 min, then brought to ambient temperature. The mixture was quenched with saturated aqueous NH4Cl (14 mL), stirred at ambient temperature for 15 min, charged with 1M HCl (12 mL), stirred at ambient temperature for 2 min, and the organics were separated. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 20 to 100% EtOAc/hexane to give 503 mg (50%) of [2-methyl-4-(methylthio)phenyl]boronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, 1H, J=7.8 Hz), 7.09-7.00 (m, 2H), 2.61 (s, 3H), 2.46 (s, 3H); LRMS (ESI), m/z 183 (M+H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:16][CH2:15]2)[C:7]1=[O:17])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[N+:18]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7](=[O:17])[C:8]12[CH2:16][CH2:15]1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CCCCCN1C(=O)C2(CC2)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CCCCCN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Reaction time: 3 h

Procedure:
1′-Pentyl-spiro[cyclopropane-1,3′-indoline]-2′-one (24.8 g) is suspended in acetic acid (250 ml) and nitric acid (fuming, 11.9 ml) is added over a period of 15 min at 15° C. The mixture is stirred for 3 h, diluted with water and extracted with Et2O (3×300 ml). The combined organic layer is washed with water, saturated K2CO3 solution and brine, dried over MgSO4 and evaporated to give the compound (29.3 g).
Reaction SMILES: S(Cl)(N=C=O)(=O)=O.C1(CO)C=CC=CC=1.Cl.[CH3:17][CH:18]1[CH2:21][NH:20][CH2:19]1.Cl[S:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:25])=[O:24]>C(OC(C)C)(=O)C.C(N(CC)CC)C.C(#N)C>[CH3:17][CH:18]1[CH2:21][N:20]([S:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:24])=[O:25])[CH2:19]1
Reactant: CC1CNC1
Reactant: O=C(NS(=O)(=O)Cl)OCc1ccccc1
Agent: Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: CC(=O)OC(C)C
Solvent: OCc1ccccc1
Solvent: CCN(CC)CC
Product: CC1CN(S(=O)(=O)NC(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
Isopropyl acetate (300 mL) was charged into a 1000 ml 3-neck flask and cooled to −10˜−5° C. Sulfurisocyanatidic chloride (44.5 mL) was added at −5˜10° C. followed by the addition of phenylmethanol (50.5 mL) in isopropyl acetate (60 mL) at −5˜10° C. over 60 minutes. The mixture reacted at −5˜10° C. and was monitored by HPLC until the content of benzyl alcohol was <2% (after 1 hour at 0° C.). A mixture of acetonitrile (300 mL), 3-methylazetidine hydrochloride (50 g) (Intermediate C, either commercially available or prepared as set out below) and triethylamine (162 mL) was stirred in a 2000 mL 3-neck flask and to this was added the solution of the intermediate benzyl chlorosulfonylcarbamate in isopropyl acetate (360 mL) dropwise at <−5° C. over 90 minutes. The mixture was allowed to warm to RT overnight. The reaction was quenched with acetic acid and pH was adjusted to 4˜5. The mixture was separated and the aqueous phase was washed with isopropyl acetate (500 ml) and then separated. The organic phase was combined and washed with 10% brine (2×120 ml), dried with anhydrous magnesium sulphate, filtered and the filter cake washed with isopropyl acetate (30 ml) and filtered to afford the sub-title product (145 g) as a red oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OCC)(=O)C>C(Cl)Cl.CS(C)=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][CH:19]=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(CCCO)c1ccc(Oc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CCCS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Part D: A cooled solution of 13 g (44 mmol) of 3-[(4-phenoxyphenyl)sulfonyl]propan-1-ol from Part C in 60 mL of anhydrous CH2Cl2 was treated with 25 mL (18 g, 178 mM) of triethylamine. The reaction mixture was then treated with a slurry of 28 g (178 mM) of pyridine-SO3 complex in 60 mL of methyl sulfoxide added over one-half hour. After stirring for one hour, the reaction mixture was poured over 500 mL of ice and ethyl acetate was added. The layers were separated and the organic layer was washed with 5% KHSO4 solution, water and brine, dried (MgSO4), and concentrated to afford 13 g of 3-[(4-phenoxyphenyl)sulfonyl]propan-1-al, suitable for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C@H:24]1[NH:29][C@@H:28]([CH3:30])[CH2:27][N:26]([CH2:31][C:32]2[C:33]([CH3:40])=[C:34]([CH:38]=O)[NH:35][C:36]=2[CH3:37])[CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:38]\[C:34]1[NH:35][C:36]([CH3:37])=[C:32]([CH2:31][N:26]2[CH2:25][C@H:24]([CH3:23])[NH:29][C@H:28]([CH3:30])[CH2:27]2)[C:33]=1[CH3:40])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the tiled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([Cl:33])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[C:25]([Cl:33])[CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: FC(F)(F)c1ccc(Br)cc1Cl
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: O=C1N(c2ccc(C(F)(F)F)c(Cl)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 148 step E or example 179 step A for an alternative synthesis) and 4-bromo-2-chloro-1-trifluoromethyl-benzene. Off-white solid. MS (ESI): 507.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[C:25](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (1.37 g, 4.1 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (1.35 g, 4.1 mmol) and methyliodide (587 mg, 0.26 mL, 4.1 mmol) and the resulting mixture stirred for 30 min. The resulting mixture was then evaporated and extracted with ethyl acetate and water. The organic extract was then washed with water, brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 2:3) afforded the title compound (730 mg, 51%) which was obtained as a colorless oil. MS: m/e=346.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][SH:12])=[O:10])[CH2:2][O:3][C:4]([CH2:6][SH:7])=[O:5].C1CCC(O)([C:19]([C:21]2[CH:26]=CC=C[CH:22]=2)=[O:20])CC1>>[CH2:2]([O:3][C:4]([CH2:6][SH:7])=[O:5])[CH2:1][O:8][C:9]([CH2:11][SH:12])=[O:10].[C:19]([OH:3])(=[O:20])[C:21]([CH3:26])=[CH2:22]
Reactant: O=C(c1ccccc1)C1(O)CCCCC1
Agent: O=C(CS)OCCOC(=O)CS
Product: C=C(C)C(=O)O

Procedure:
GDMA (556.8 g, 5.15 eq.) was weighed into a 2000 ml, three neck, round bottom flask. MAA (442.9 g, 5.15 eq.) and Irgacure 184 (1.5 g) were weighed into a 500 ml addition funnel equipped with a Teflon stop cock.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][O:9][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1COC1CCCCO1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 25 parts of 5-chloro-2-nitrobenzenemethanol, 13.3 parts of dihydro-2H-pyran, 300 parts of dichloromethane and 0.28 parts of 4-methylbenzenesulfonic acid was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was neutralized with sodium carbonate and stirred for 10 min. The whole was filtered and the filtrate was evaporated. The residue was co-evaporated with methylbenzene and then purified by columns chromatography (silica gel; CHCl3). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene, yielding 36 parts (99.6%) of 2-[(5-chloro-2-nitrophenyl)methoxy]tetrahydro-2H-pyran (interm. 1).
Reaction SMILES: Cl.[OH:2][C:3]1([C:15]2[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=2)[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]#[N:14])[CH:6]=[CH:5][C:4]1=2>O1CCCC1>[OH:2][C:3]1([C:15]2[NH:16][CH:17]=[N:18][CH:19]=2)[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]#[N:14])[CH:6]=[CH:5][C:4]1=2
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CCCC2(O)c1cnc[nH]1
Temperature: 25 °C

Procedure:
3 ml of 2M HCl are added to a solution of 1 mmol of 5-hydroxy-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (Example 1d1) in 15 ml of tetrahydrofuran, and the mixture is heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and evaporated. The residue is mixed with 1M sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[OH:12][CH:13]([N:26]1[C:32](=[O:33])[C@@H:31]2[C@H:27]1[S:28][C:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[N:30]2)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC1(C)S[C@@H]2[C@H](NC(COC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>O.ClCCl.CC(C)=O>[OH:12][CH:13]([N:26]1[C@H:27]([SH:28])[C@H:31]([NH:30][C:29](=[O:8])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]1=[O:33])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@H]3N=C(Cc4ccccc4)S[C@H]32)cc1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Toluene-4-sulphonic acid (6.0 g, 31.5 mmol) in water (15 ml) was added to a solution of 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo [3.2.0]hept-2-en-7-on-6-yl]acetate (7.42 g, 18.0 mmol) prepared from Penicillin G as described for the benzhydryl ester derived from Penicillin V, S. Yamamoto, N. Haga, T. Aoki, S. Hayashi, H. Tanida, and W. Nagata, Heterocycles, 1977, 8, 283) in dichloromethane (30 ml) and acetone (30 ml). After stirring for 2.5 h at room temperature, the reaction mixture was diluted with dichloromethane, washed with water (x2), dried and concentrated in vacuo to yield crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R, 4R) -4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate as a yellow foam.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:29](=[O:69])[NH:30][C@H:31]([C:58](=[O:68])[NH:59][C:60]3[CH:65]=[CH:64][C:63]([CH2:66][OH:67])=[CH:62][CH:61]=3)[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C1COCC1>[OH:67][CH2:66][C:63]1[CH:62]=[CH:61][C:60]([NH:59][C:58](=[O:68])[C@@H:31]([NH:30][C:29](=[O:69])[C@@H:18]([NH2:17])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:65][CH:64]=1
Reactant: COc1ccc(C(NCCCC[C@H](NC(=O)[C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)Nc2ccc(CO)cc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: COc1ccc(C(NCCCC[C@H](NC(=O)[C@@H](N)Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(CO)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
In a 50 mL round-bottomed flask, the above prepared [(S)-1-((S)-1-(4-hydroxymethyl-phenylcarbamoyl)-5-{[(4-methoxy-phenyl)-diphenyl-methyl]-amino}-pentylcarbamoyl)-2-(4-nitro-phenyl)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (1.214 g, 1.29 mmol, Eq: 1.001) was combined with THF (19 ml) to give a brown solution. At 0°, diethylamine (1.77 g, 2.49 ml, 24.2 mmol, Eq: 18.70) was added. The reaction was stirred at ambient temperature for 3 h when MS indicated the disappearance of the starting material. All volatiles were evaporated i. V.; ensuing flash chromatography SiO2/0.1% NEt3 in CH2Cl2=>10% MeOH/0.1% NEt3 in CH2Cl2, followed by a second flash chromatography SiO2/5% MeOH/0.1% NEt3 in CH2Cl2 afforded 502 mg of the title compound as light brown foam. MS: expected mass: 715.337, found mass: 715.3362.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[C:5]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=1)([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Reaction time: 20 h

Procedure:
2-(4-Trifluoromethylphenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(S(C)(=O)=O)cc2)c1C(=O)OC
Yield: 104 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.3 g, 6.1 mmol) in acetone (25 mL) and potassium carbonate (2.5 g, 18 mmol) was added 1-bromomethyl-4-methanesulfonyl-benzene (1.6 g, 6.4 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(4-methanesulfonyl-benzyloxy)-phthalic acid dimethyl ester (2.4 g, 104% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH2:37][CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[CH2:37][CH3:38])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCC(O)c1ccccc1Cl
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(=O)OC)c1ccccc1Cl

Procedure:
In a similar manner as described for example B31, 3.0 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.83 g of 1-(2-chlorophenyl)propan-1-ol, 4.76 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 3.29 g of di-tert-butyl azodicarboxylate in 85 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([CH3:23])=[C:16]([CH:18](OC)[O:19]C)[CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:24]>Cl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]=[O:19])[C:15]([CH3:23])=[N:14][CH:13]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:24]
Reactant: CC[C@@H](Nc1cnc(C)c(C(OC)OC)c1)c1ccc(Cl)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC[C@@H](Nc1cnc(C)c(C=O)c1)c1ccc(Cl)c(C)c1

Procedure:
INT 49 (184 mg, 0.527 mmol) was heated at 80° C. in 1 M HCl (2.6 mL) for 2 hours. The mixture was cooled down and diluted with saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over sodium sulfate and concentrated. The product was used in the next step without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][NH2:28])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl.O.CO>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][NH:28][C:1](=[O:3])[CH3:2])[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
Acetic anhydride (0.40 mL, 0.43 g, 4.2 mmol) was added to a stirred, cooled (0° C.) solution of 2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine (1.02 g, 3.5 mmol), 4-dimethylaminopyridine (86 mg, 0.7 mmol) and pyridine (0.57 mL, 0.55 g, 7 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 1 h. Methanol (1 mL) was added and the mixture was stirred at room temperature for 2 h. Aqueous sodium hydrogen carbonate (saturated, 20 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (99.5:0.5:0.05 increasing to 98:2:0.2) to give the title compound as a colorless solid (681 mg, 58%), δH (250 MHz, CDCl3) 7.28 (2H, m), 7.12 (2H, m), 6.26 (1H, br s), 4.55 (2H, d, J 5.6 Hz), 3.57 (4H, t, J 4.9 Hz), 2.86 (4H, t, J 4.9 Hz), 2.03 (3H, s), and 1.49 (9H, s). m/e (ES+) 334 (MH+).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>CN(C)C=O>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][CH2:37][CH2:36][N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:20])=[CH:14][CH:13]=2)[CH:18]=[C:10]1[C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]1)=[O:9])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc21
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and (2-bromoethoxy)-tert-butyldimethylsilane (commercially available) in N,N-dimethylformamide, to give the desired product as a colorless oil (44%).