Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[C:53]5=[N:54][O:55][N:56]=[C:52]5[C:51]([N+:57]([O-:59])=[O:58])=[CH:50][CH:49]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[C:53]5=[N:54][O:55][N:56]=[C:52]5[C:51]([N+:57]([O-:59])=[O:58])=[CH:50][CH:49]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a slurry of N-[3-({3-[(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}amino)-3-oxopropyl]-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (24, 29 mg, 0.028 mmol) and K2CO3 (76 mg, 0.552 mmol) in N,N-dimethylformamide (6 mL) and tetrahydrofuran (2 mL) was added thiophenol (40 μL, 0.389 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. Purification by preparative reverse-phase HPLC (gradient: 59.9% MeCN, 40% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 14 min; retention time =10.6 min) afforded 6 (15 mg, 52%) mp 170-171° C.; 1H NMR (500 MHz, CDCl3) δ 9.54 (br s, 1H), 8.68 (br s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.07 (t, J=5.35, 1H), 7.92 (t, J=5.4 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 6.40 (d, J=8.9 Hz, 1H), 5.36 (m, 1H), 3.43 (m, 1H), 3.24-3.17 (m, 4H), 3.10 (m, 2H), 2.88 (br s, 3H), 2.35 (d, J=7.2 Hz, 2H), 2.23 (t, J=6.9 Hz, 2H), 2.18 (t, J=7.1 Hz, 2H), 2.04 (t, J=7.2 Hz, 2H), 1.94-0.96 (m, 35H), 0.93 (s, 3H), 0.86 (d, J=6.2 Hz, 3H), 0.84 (d, J=2.1 Hz, 3H), 0.82 (d, J=2.1 Hz, 3H), 0.62 (s, 3H); 13C NMR (125.8 MHz, DMSO d6) δ 171.9, 170.8, 170.3, 145.1, 144.4, 144.2, 138.6, 137.9 122.3, 120.5, 99.1, 56.6, 56.1, 55.5, 49.3 (×2), 45.5. 43.3, 41.8 (×2), 41.5, 36.4, 36.2, 35.6 (×2), 35.5 (×2), 35.3 (×2), 35.2, 35.1, 34.3, 31.2, 27.7, 27.4, 27.3, 26.2, 26.0, 24.9, 24.3, 23.8, 23.2, 22.6, 22.4, 20.5, 18.8, 18.5, 11.6; IR (film) νmax 3173, 3075, 2919, 2848, 1634, 1538, 1331 cm−1; CI m/z 861.5965 (MH+, C48H77N8O6 requires 861.5966).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]=2[CH2:18][CH2:19][CH3:20])=[O:12])=[CH:4][C:3]=1[CH3:25].Cl[CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+].O>[OH:31][C@@H:28]([CH2:29][OH:30])[CH2:27][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]=2[CH2:18][CH2:19][CH3:20])=[O:12])=[CH:4][C:3]=1[CH3:25]
Reactant: OC[C@H](O)CCl
Reactant: CCCc1c(CC(C)C)csc1C(=O)CCc1cc(C)c(O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCc1c(CC(C)C)csc1C(=O)CCc1cc(C)c(OC[C@@H](O)CO)c(C)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 13.8 %

Procedure:
To a solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-isobutyl-3-propyl-thiophen-2-yl)-propan-1-one (108 mg, 0.301 mmol) in isopropanol (5 mL), 3 N aq. NaOH (3 mL) followed by (S)-3-chloro-1,2-propanediol (167 mg, 1.51 mmol) is added. The mixture is stirred at 70° C. for 4 h. After 4, 5, 6, 7 and 8 h an additional portion of (S)-3-chloro-1,2-propanediol (5×97 mg, 0.878 mmol) is added. After the last addition, stirring is continued at 60° C. for 16 h. The mixture is diluted with water and extracted with diethyl ether. The organic extract is dried over MgSO4, filtered and evaporated. The crude product is purified by prep. HPLC to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-isobutyl-3-propyl-thiophen-2-yl)-propan-1-one (18 mg) as an almost colourless resin; LC-MS: tR=1.09 min, [M+1]=433.40; 1H NMR (CDCl3): δ 7.08 (s, 1H), 6.87 (s, 2H), 4.11-4.03 (m, 1H), 3.90-3.70 (m, 4H), 3.14-3.06 (m, 2H), 2.94-2.82 (m, 4H), 2.60 (s br, 2H), 2.40 (d, J=7.0 Hz, 2H), 2.24 8s, 6H), 1.90-1.78 (m, 1H), 1.56-1.46 (m, 2H), 1.00 8t, J=7.0 Hz, 3H), 0.93 (d, J=6.4 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[NH:30][CH2:31][CH2:32][N:33]=2)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH:30]1[CH2:31][CH2:32][N:33]=[C:29]1[C:25]1[CH:24]=[C:23]([O:1][C:2]2[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=3)=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Clc1ccnc(C2=NCCN2)c1
Reactant: CC(C)c1cccc(NC(=O)/C=C/c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(NC(=O)/C=C/c2cccc(Oc3ccnc(C4=NCCN4)c3)c2)c1
Temperature: 100 °C

Procedure:
To a solution of (E)-3-(3-hydroxyphenyl)-N-(3-isopropylphenyl)acrylamide (3.20 mmol) in DMF (40 mL) was added 4-chloro-2-(4,5-dihydro-1H-imidazol-2-yl)pyridine (11.2 mmol) and cesium carbonate (16.0 mmol). The heterogeneous mixture was heated at 100° C. for 18 h and then cooled to rt. The mixture was diluted with water and extracted with EtOAc. The combined organic solutions were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (90:10:1 DCM:MeOH:NH4OH) to give B-2. 1H NMR (300 MHz, d6-DMSO): δ 10.13 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 7.56-7.61 (m, 3H), 7.50-7.54 (m, 2H), 7.44-7.47 (m, 1H), 7.41 (d, J=2.8 Hz, 1H), 7.20-7.29 (m, 2H), 7.17 (dd, J=6.8, 2.8 Hz, 1H), 6.93-6.99 (m, 2H), 6.85 (d, J=15.6 Hz, 1H), 3.32 (s, 4H), 2.85 (sept, J=6.8 Hz, 1H), and 1.18 (d, J=7.2 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:3]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([CH3:29])[C:25]([CH3:30])=[N:24]3)=[CH:19][C:18]=2[CH3:31])=[C:4]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH3:31][C:18]1[CH:19]=[C:20]([N:23]2[C:27]([CH3:28])=[C:26]([CH3:29])[C:25]([CH3:30])=[N:24]2)[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:3]1[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(Br)cccc1-n1nnn(C)c1=O
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(C#C[Si](C)(C)C)cccc1-n1nnn(C)c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 32.2 %

Procedure:
A mixture of 1-{3-bromo-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 70) 0.3 g, trimethylsilylacetylene 0.2 g, tetrakis triphenylphosphine palladium 0.05 g, tri-tert-butylphosphine 0.07 g, potassium phosphate 0.6 g, 1,4-dioxane 5 ml and water 0.5 ml was stirred at 100° C. for five hours. After cooling, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-3-trimethylsilylethynyl-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one 0.1 g.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][N:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH:31]3[C:44]4[C:43](=[O:45])[CH2:42][C:41]([CH3:47])([CH3:46])[CH2:40][C:39]=4[O:38][C:37]4[CH2:36][C:35]([CH3:49])([CH3:48])[CH2:34][C:33](=[O:50])[C:32]3=4)[CH:24]=2)[N:18]=1)[NH2:16].N12CCCN=C1CCCCC2.[Cl-].[NH4+]>C1COCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]3[NH:16][C:1](=[O:2])[O:13][N:14]=3)[N:18]=2)=[CH:24][C:25]=1[CH:31]1[C:32]2[C:33](=[O:50])[CH2:34][C:35]([CH3:49])([CH3:48])[CH2:36][C:37]=2[O:38][C:39]2[CH2:40][C:41]([CH3:46])([CH3:47])[CH2:42][C:43](=[O:45])[C:44]1=2
Reactant: COc1ccc(-c2cccc(C(N)=NO)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(-c3noc(=O)[nH]3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 2 h
Yield: 69.6 %

Procedure:
1,1′-Carbonyldiimidazole (173 mg, 1.07 mmol) was added to a solution of the N′-hydroxy-6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboximidamide produced in Example 8-1 (424 mg, 0.82 mmol) in THF (8.5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.160 ml, 1.07 mmol) was added to the resulting solution, and the mixture thus obtained was then stirred for 4.5 hours. Subsequently, an aqueous solution of ammonium chloride was added to the reaction solution, and the mixed solution was then extracted with dichloromethane twice. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel thin-layer chromatography (methanol:dichloromethane=1:10, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (309 mg, yield: 69%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Cl.NC(N)=N.C[O-].[Na+].[NH:13]([CH:20]=[C:21]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)[C:22]#N)C1C=CC=CC=1>C(O)C.COCCO>[NH2:3][C:2]1[N:4]=[C:20]([NH2:13])[C:21]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)=[CH:22][N:1]=1
Reactant: Cn1cc(CC(C#N)=CNc2ccccc2)c2ccccc21
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: CCO
Product: Cn1cc(Cc2cnc(N)nc2N)c2ccccc21
Yield: 41 %

Procedure:
To 100 mL of an ethanolic guanidine solution prepared from 2.10 g (0.022 mole) of guanidine hydrochloride and 1.20 g (0.022 mole) of sodium methoxide was added 5.00 g (0.017 mole) of 3-anilino-2-(1-methyl-3-indolylmethyl)acrylonitrile. The solution was heated under reflux for 1/2 hour and then 100 mL of 2-methoxyethanol was added. The internal temperature was allowed to gradually increase to 120° by distillation of the ethanol, after which it was heated at this temperature for 4.75 hr. The reaction was cooled and the solvent was removed in vacuo. The residue was recrystallized from 95% ethanol to give two crops of the title compound (total 1.82 g, 41%) mp 253°-256° dec. Anal. Calcd for C14H15N5 : C, 66.38, H, 5.97; N, 27.65. Found: C, 66.05; H, 6.04; N, 27.89.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:15]([C@@H:22]1[CH2:27][C@@H:26]([N:28]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[CH:38][CH:37]=2)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:25][CH2:24][NH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>>[CH2:15]([C@@H:22]1[CH2:27][C@@H:26]([N:28]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=[CH:38][CH:37]=2)[C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])[CH2:25][CH2:24][N:23]1[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1cccc(Br)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Br)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 94.9 %

Procedure:
141 mg (0.70 mmol) of m-bromobenzoic acid are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 118 μl (0.842 mmol) of triethylamine to give the title compound (271 mg, 95%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.71, FD-MS: M+ =609, 611.
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[O:16])=[CH:9][CH:8]=1)=O)C.CC(C)=O.N>N1C=CC=CC=1>[OH:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[O:16])=[CH:9][CH:8]=1
Reactant: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(OC(=O)OCC)cc1
Agent: N
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 g of 4-methacryloyloxybutyl (E)-3-(4-ethoxycarbonyloxyphenyl)acrylate were dissolved in 40 ml of pyridine and treated at room temperature with a mixture of 60 ml of acetone and 7 ml of 25% aqueous ammonia solution. The reaction mixture was stirred at room temperature for 12 hours. After distillation of the acetone the mixture was neutralized with 2N hydrochloric acid, diluted with 100 ml of water and subsequently extracted 3 times with 100 ml of diethyl ether each time. The combined organic phases were dried over sodium sulphate, filtered and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 7:3) gave 4-methacryloyloxybutyl (E)-3-(4-hydroxyphenyl)acrylate.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:45]=[C:46]([CH:54]=[CH:55][CH:56]=1)[CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(C(C)C)CC)(C)C>ClCCl>[O:17]=[C:15]([N:51]1[CH2:50][CH2:49][N:48]([CH2:47][C:46]2[CH:54]=[CH:55][CH:56]=[C:44]([C:43]([F:57])([F:58])[F:42])[CH:45]=2)[CH2:53][CH2:52]1)[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
To 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.057 g, 0.244 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.098 g, 0.257 mmol) and 1-(3-(trifluoromethyl)benzyl)piperazine (0.066 g, 0.269 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.064 mL, 0.367 mmol) and the reaction was allowed to stir at room temperature. After stirring overnight, the reaction was loaded directly onto a silica gel column (Analogix®, SF15-12), and the product was eluted using a gradient of 0.4% to 3.75% methanol/dichloromethane over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.58-7.60 (br s, 1H), 7.49-7.55 (m, 2H), 7.41-7.47 (m, 1H), 7.27-7.35 (m, 3H), 7.18-7.26 (m, 2H), 4.47 (d, J=15.7 Hz, 1H), 4.03 (d, J=15.7 Hz, 1H), 3.68-3.73 (m, 1H), 3.59-3.67 (m, 2H), 3.56-3.62 (m, 1H), 3.53-3.59 (m, 2H), 3.47-3.52 (m, 2H), 3.39-3.45 (m, 1H), 2.42-2.49 (m, 4H), 2.17-2.28 (m, 1H), 1.87-2.05 (m, 3H); MS (ESI−) m/z 458 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 55.9 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (29-03) (3.5 g, 55.85%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (28-02) (4.3 g, 9.817 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8-b) (2.34 g, 10.79 mmol) as a colourless gummy solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[C:6]=1[F:16])[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[C:6]=1[F:16])[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1F
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-fluoro-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[C:15]2[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=2[C:17]2[CH2:18][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:20](=[O:23])[C:21]=2[CH:22]=1.IC.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[C:15]2[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=2[C:17]2[CH:18]([CH3:1])[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:20](=[O:23])[C:21]=2[CH:22]=1
Reactant: CC(C)NC(C)C
Reactant: O=C1c2cc(Br)c3ccccc3c2CN1c1ccccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2c(cc(Br)c3ccccc23)C(=O)N1c1ccccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.30 mL, 2.1 mmol) in 1 mL of tetrahydrofuran cooled to 0° C. was added n-butyllithium (2.5 M tetrahydrofuran solution, 0.93 mL, 2.3 mmol) dropwise. After 30 min, the mixture was added to a −78° C. solution of 5-bromo-2-(2-fluorophenyl)-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.150 g, 0.421 mmol) in 2 mL of tetrahydrofuran. After stirring for 30 min at −78° C., iodomethane (0.026 mL, 0.42 mmol) was added dropwise and after an additional 1 hr, the mixture was warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted 2× with ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the 5-bromo-2-(2-fluorophenyl)-1-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one that gave a proton NMR spectra consistent with theory.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:23])[S:8](=[O:22])(=[O:21])[C:9]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])=O)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(Cl)CCl>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:4]([C:6]2[N:7]([CH3:23])[S:8](=[O:21])(=[O:22])[C:9]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][C:10]=3[C:11]=2[OH:12])=[O:3])[CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1cccc(Cl)c1
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2cccc(Cl)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 71 %

Procedure:
N-(3-Chloro-phenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid ethyl ester-1,1-dioxide and 3-chloroaniline. Yield: 71% of theory; m.p. 248°-249° C (decomp.; from ethylene chloride).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]([F:17])([F:16])[CH2:7][C:8]1[N:9]=[C:10]([N+:13]([O-:15])=[O:14])[NH:11][CH:12]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)(Cl)Cl>[N+:13]([C:10]1[NH:11][CH:12]=[C:8]([CH2:7][C:6]([F:17])([F:16])[C:5]([NH:4][CH2:3][CH2:2][O:1][C:26]([O:28][CH3:29])=[O:27])=[O:18])[N:9]=1)([O-:15])=[O:14]
Reactant: O=C(NCCO)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)OCCNC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1

Procedure:
3-(2'-Nitroimidazolyl)-2,2-difluoropropionic acid hydroxyethylamide (6.0 g, 22.7 mmol) was dissolved in a solvent mixture of methyl chloroformate (30 ml) and chloroform (30 ml) and cooled by ice. To the solution, a solution of pyridine (6.0 ml) in chloroform (30 ml) was dropwise added over 2 hours. The completion of the reaction was confirmed by thin-layer chromatography. Then, the reaction solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography to obtain methyl 3-(2'-nitroimidazolyl)-2,2-difluoropropionamidoethoxyformate (6.89 g). m.p. 50.5°-52.5° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.C1(COC2N=C(C(O)=O)C=CC=2C2CCCO2)CC1.[NH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42]>>[OH:42][CH2:41][C:40]([NH:39][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:44])[CH3:43]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Agent: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Product: CC(C)(CO)NC(=O)c1ccc(C2CCOC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (mixture from Example 114 d), and 2-amino-2-methyl-1-propanol (CAN 124-68-5) as starting materials, MS (EI): m/e=335.1 [M+H]+.