Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[O:28])=[C:18]([CH:26]=2)[O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:39][OH:40].[O-]CC.[Na+:44]>C(O)C>[Na+:44].[NH2:2][C:1](=[N:39][OH:40])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:30]([CH3:32])[CH3:31])[CH:33]([CH3:35])[CH3:34])=[O:28])=[C:18]([CH:26]=2)[O:19][C:20]([CH3:25])([CH3:24])[C:21]([O-:23])=[O:22])=[CH:36][CH:37]=1
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1OC(C)(C)C(=O)O)C(C)C
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C(N)=NO)cc2)cc1OC(C)(C)C(=O)[O-])C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A stirred solution of 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-2-methylpropionic acid (1.4 g, 2.8 mmol) in 30 mL of anhydrous ethanol is treated with hydroxylamine hydrochloride (590 mg, 8.4 mmol) and 21% sodium ethoxide solution in ethanol (3.1 mL, 5.7 mmol) and stirred at 50° C. overnight. The reaction is concentrated in vacuo and purified by chromatography on silica gel (20 g) with 80-100% ethyl acetate/hexane followed by 0-10% methanol/ethyl acetate as the eluent to afford 2-[5-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]2-[N,N-bis(1-methylethyl) -aminocarbonyl]phenoxy]-2-methylpropanoic acid sodium salt as a colorless foam;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:22]([C:24]1[N:29]=[C:28]2[CH2:30][O:31][C:32](=O)[C:27]2=[CH:26][CH:25]=1)=[CH2:23].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:32]1[C:27]2[C:28](=[N:29][C:24]([CH:22]=[CH2:23])=[CH:25][CH:26]=2)[CH2:30][O:31]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: C=Cc1ccc2c(n1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (1.13 g, 7.44 mmol) in THF (70 mL) is placed under an Argon atmosphere and cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (14.9 mL of a 1.0 M solution in THF, 14.9 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. Solid 2-vinyl-7H-furo[3,4-b]pyridin-5-one (600 mg, 3.72 mmol) is added in one portion. The reaction mixture is stirred for 4.5 h and then poured into an aqueous 1N HCl solution (150 mL). The resulting mixture is stirred at room temperature for 70 h during which time a yellow solid precipitated from solution. The solid is collected by filtration and washed with aqueous 10% HCl solution, MeOH (3×5 mL) and Et2O (3×5 mL). The solid is dried under vacuum overnight to give the title compound (260 mg, 24%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>CCCCCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:19])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cl)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
13bk) 49.4 g of 4-bromo-2-chloro-benzoic acid were suspended in 60 ml of hexane, treated with 0.2 ml of N,N-dimethylformamide and 18.5 ml of thionyl chloride and boiled at reflux under argon for 15 hrs. The resulting solution was cooled to room temperature, filtered, evaporated and the residue was again evaporated with 60 ml of toluene. There were obtained 53 g (99%) of 4-bromo-2-chloro-benzoylchloride as a crude oil which crystallized upon standing, but which was used directly in the next step without further manipulation.
Reaction SMILES: N(CCO)(CCO)CC[OH:4].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.O.[N:19]([CH2:26][CH2:27][OH:28])([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>O>[C:11]([OH:16])(=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:4])=[O:15].[N:19]([CH2:26][CH2:27][OH:28])([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]
Reactant: O=C1C=CC(=O)O1
Solvent: O
Solvent: OCCN(CCO)CCO
Product: O=C(O)/C=C\C(=O)O
Temperature: 50 °C

Procedure:
Triethanolamine (99% pure, Aldrich) and water as specified in Table 2 was added into a 500 ml beaker for each of the following examples. The beaker was heated to 50° C. on a hot plate with magnetic agitation. A preweighed amount of maleic anhydride briquett (100%, Huntsman) was then added to the triethanolamine water solution. After all the maleic anhydride was dissolved, the mixture was cooled and was ready for further blending.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].FC(F)(F)C(O)=O.[CH3:64][C:65]1[CH:66]=[N:67][C:68]2[NH:69][C:70]3[CH:71]=[N:72][CH:73]=[C:74]([CH:87]=3)[CH2:75][CH2:76][C:77]3[CH:85]=[C:81]([NH:82][C:83]=1[N:84]=2)[CH:80]=[CH:79][C:78]=3[NH2:86]>CN(C)C=O.C(N(CC)C(C)C)(C)C>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:86][C:78]3[CH:79]=[CH:80][C:81]4[NH:82][C:83]5[N:84]=[C:68]([NH:69][C:70]6[CH:71]=[N:72][CH:73]=[C:74]([CH:87]=6)[CH2:75][CH2:76][C:77]=3[CH:85]=4)[N:67]=[CH:66][C:65]=5[CH3:64])=[O:18])[CH2:13][CH2:14]2)=[O:8])[CH:3]=1
Reactant: Cc1cc(C(=O)N2CCC(CC(=O)O)CC2)no1
Reactant: Cc1cnc2nc1Nc1ccc(N)c(c1)CCc1cncc(c1)N2
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: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(C)c(n3)N4)CC2)no1
Reaction time: 8 h
Yield: 3.4 %

Procedure:
A solution of {1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}acetic acid (4.8 mg, 0.019 mmol) (prepared in Example C49, step I), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (19 mg, 0.050 mmol) in N,N-dimethylformamide (0.2 mL) and N,N-diisopropylethylamine (7.6 uL) was stirred for 15 minutes. A solution of 6-methyl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) (6.0 mg, 0.019 mmol) (prepared in Example C29, step C) in N,N-dimethylformamide (0.1 mL) and was added to the previous solution and was stirred overnight. The reaction mixture was purified by preparative HPLC (pH 2) to give the desired product (0.5 mg, 19%). LCMS for C30H33N8O3 (M+H)+: m/z=553.2. 1H NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 9.38 (s, 1H), 9.34 (s, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.00 (dd, J=8.3, 2.2 Hz, 1H), 6.41 (dd, J=8.1, 0.8 Hz, 1H), 4.42 (m, 4H), 3.86 (m, 4H), 2.90-3.10 (m, 6H), 2.10-2.30 (m, 4H), 2.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:12]([Cl:13])=[CH:11][C:10]([N:14]3[C:19](=[O:20])[NH:18][CH2:17][CH:16]=[N:15]3)=[CH:9][C:8]=2[Cl:21])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:12]([Cl:13])=[CH:11][C:10]([N:14]3[C:19](=[O:20])[NH:18][C:17](=[O:25])[CH:16]=[N:15]3)=[CH:9][C:8]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: O=C1NCC=NN1c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=c1cnn(-c2cc(Cl)c(Cc3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 2.6 g of 2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one. To the solution was added 4.5 g of pyridinium chlorochromate. The mixture was stirred at room temperature overnight, after which the insoluble matter was filtered off. The filtrate was concentrated. The residue was purified by column chromatography (Merck Silica Gel 60; chloroform-ethanol=20:1) to provide 2.2 g of the title compound as colorless crystals, m.p. 175-176° C.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].CO.I[CH2:16][CH2:17][CH2:18][CH3:19]>O.Cl>[CH2:16]([N:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]1=[O:1])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1cccnc1O
Reactant: CCCCI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCn1cccc(C(=O)O)c1=O
Temperature: 60 °C
Yield: 38.5 %

Procedure:
To a solution of 2-hydroxy-nicotinic acid (0.50 g, 3.59 mmol) and potassium -hydroxide (0.40 g, 7.13 mmol) in 4:1 methanol: water (6 mL) at room temperature, was added 1-iodobutane (0.74 mL, 6.42 mmol). This solution was heated at 60° C. for 30 minutes, then cooled to room temperature and diluted with water and 1N HCl. The resulting solid was filtered and dried to give the title compound (0.27 g, 39%). MS (DCI/NH3) m/z 196 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.91 (m, 3 H) 1.30 (m, 2 H) 1.69 (m, 2 H) 4.10 (m, 2 H) 6.73 (m, 1 H) 8.27 (dd, J=6.62, 1.84 Hz, 1 H) 8.38 (dd, J=7.35, 2.21 Hz, 1 H) 14.68 (s, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[CH2:5]1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[N:17]1([CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[CH2:5]2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CN1CC(CCCl)Cc2ncccc2C1=O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN1CC(CCn2ccnc2)Cc2ncccc2C1=O
Temperature: 130 °C

Procedure:
To a solution of 8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one in dimethylformamide (DMF) is added imidazole. The solution is heated to about 130° C. for several hr. DMF is removed by evaporation in vacuo and the residue is taken up in chloroform. The chloroform solution is washed with dilute aqueous sodium hydroxie, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[Si:18]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl 4-hydroxycyclohexanecaboxylate (3.44 g, 20.0 mmol) was dissolved in DMF (7 mL), and imidazole (3.40 g, 50.0 mmol) and tert-butyldimethylsilyl chloride (3.62 g, 24 mmol) were added thereto, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=10:1) to afford ethyl 4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylate (5.73 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].[CH2:21]([Li])[CH2:22][CH2:23][CH3:24].[CH2:26]([OH:37])[C@H:27]1[O:33][C:31](=[O:32])[C@H:30]([OH:34])[C@@H:29]([OH:35])[C@@H:28]1[OH:36]>O1CCCC1>[CH2:21]([O:34][C@@H:30]1[C@@H:29]([O:35][CH2:21][C:22]2[CH:11]=[CH:10][CH:12]=[CH:24][CH:23]=2)[C@H:28]([O:36][CH2:21][C:22]2[CH:14]=[CH:13][CH:15]=[CH:24][CH:23]=2)[C@@H:27]([CH2:26][O:37][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][CH:19]=2)[O:33][C:31]1([C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:19]=1)[OH:32])[C:22]1[CH:18]=[CH:16][CH:17]=[CH:24][CH:23]=1
Reactant: [Li]CCCC
Reactant: CC(C)[Si](OCc1cc(Br)ccc1Cl)(C(C)C)C(C)C
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1cc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (5-Bromo-2-chlorobenzyloxy)triisopropylsilane (compound 4, 97 g, 257 mmol) from Step 3 in tetrahydrofuran (1 L) at −78° C. under an atmosphere of nitrogen was added dropwise n-butyllithium (2.5 M in hexanes, 103 mL, 257 mmol), and the mixture was stirred for 1.5 h at the same temperature. Then a solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranone (compound 2, 106 g, 198 mmol) from Step 1 in tetrahydrofuran (500 mL) was added dropwise, and the mixture was stirred for 3 h at the same temperature. The reaction mixture was quenched by addition of saturated ammonium chloride solution. After complete addition, the solution was gradually raised to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]2([C:17]([OH:19])=[O:18])[CH2:16][O:15]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12]C)=[N:5]2.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:16][C:14]([OH:15])([C:17]([OH:19])=[O:18])[C:3]=1[C:4]=23
Reactant: COc1cnc2ccc(F)c(C3(C(=O)O)CO3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1(O)Cn2c(=O)cnc3ccc(F)c1c32
Temperature: 80 °C

Procedure:
A solution of 2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-2-oxiranecarboxylic acid (3.22 g, 0.012 mol) in 1,4-dioxane (210 mL) and water (90 mL) was treated with lithium hydroxide (584 mg, 0.024 mol) dropwise at RT. The reaction mixture was heated at 80° C. for 35 hours then cooled, quenched to pH 7 with a 2M solution of hydrochloric acid and then the solvent was evaporated. The residue was placed directly onto a 100 g silica gel column and chromatographed, eluting with a 0-50% methanol in dichloromethane gradient to afford the product as a yellow solid (7.07 g of a 3:1 mixture of product/starting material).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[F:30][C:31]1[C:37]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][C:39]([F:40])([F:41])[F:42])[C:31]=2[F:30])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(OC(F)(F)F)c1F
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.83 g, 8.07 mmol) in dry THF (45 mL) at −20° C. under nitrogen atmosphere was added triethylamine (3.32 mL, 23.8 mmol) followed by ethylchloroformate (0.775 mL, 8.07 mmol) dropwise. The reaction mixture was stirred at −20° C. for 90 min and a solution of 2-fluoro-3-(trifluoromethoxy)aniline (prepared as described in Part C, 1.5 g, 7.69 mmol) in dry THF (5 mL) was added. The reaction mixture was further stirred at −20° C. for 1 h, warmed up to RT and stirred at 65° C. for 16 h until completion of the reaction. The reaction mixture was diluted with EtOAC, washed with a saturated aqueous solution of NaHCO3 (×3) and brine, dried (phase separator) and concentrated under reduced pressure. The crude residue was purified via flash column chromatography on silica gel (EtOAc/c-hexane 1:1) to give the desired material as a colorless oil. MS: 427 [M+Na]+, 304.9 [MH−Boc]+; tR (HPLC conditions c): 5.23 min.
Reaction SMILES: C1([Li])C=CC=CC=1.Br[CH:9]=[CH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1.C1C=CC=CC=1>O>[C:10]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)#[CH:9]
Reactant: COc1ccc(C=CBr)c2ccccc12
Agent: [Li]c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: C#Cc1ccc(OC)c2ccccc12

Procedure:
Phenyllithium (164 ml. of 2.1 M, 0.345 mol.) was added dropwise to a solution of 35.9 g. (0.138 mol.) of 1-(2-bromoethenyl)-4methoxynaphthalene in 120 ml. of refluxing dry benzene under a nitrogen atmosphere. After addition the reaction mixture was refluxed for 30 minutes, then ice and water were slowly added. The mixture was shaken, the layers separated and the organic phase was washed with water and saturated sodium chloride solution, dried (MgSO4) and evaporated to give 1-ethynyl-4-methoxynaphthalene.
Reaction SMILES: CC1(C)C2CC[C@@]31[C@H](C2)N([C:12](=[O:23])[C@H:13]([CH3:22])[C@H:14]([O:19][CH2:20][CH3:21])[CH2:15][CH2:16][CH:17]=[CH2:18])S(=O)(=O)C3.[OH-:27].[Li+].Cl>O1CCCC1>[CH2:20]([O:19][C@H:14]([CH2:15][CH2:16][CH:17]=[CH2:18])[C@@H:13]([CH3:22])[C:12]([OH:23])=[O:27])[CH3:21]
Reactant: C=CCC[C@@H](OCC)[C@@H](C)C(=O)N1[C@H]2CC3CC[C@@]2(CS1(=O)=O)C3(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC[C@@H](OCC)[C@@H](C)C(=O)O
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of (2R,3R)-1-((1R,5S)-10,10-dimethyl-3,3-dioxo-3lambda*6*-thia-4-aza-tricyclo[5.2.1.0*1,5*]dec-4-yl)-3-ethoxy-2-methyl-hept-6-en-1-one (245 mg, 0.64 mmol) in tetrahydrofuran (12 mL) was added a lithium hydroxide solution (2 M aqueous, 5 mL). The mixture was heated to reflux for 16 hours then cooled to room temperature and acidified to pH 1 with 2 M hydrochloric acid (15 mL). The aqueous layer was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and evaporated to give a colourless gum, which was purified by silica gel chromatography using iso-hexanes/ether 1:1 to give the title compound (78 mg, 65%) as a colourless gum. 1H NMR (300 MHz, CDCl3) δ 1.17 (d, J=7.1 Hz, 3H), 1.20 (t, J=7.5 Hz, 3H), 1.55-1.65 (m, 2H), 2.05-2.30 (m, 2H), 2.72-2.83 (m, 1H), 3.52-3.62 (m, 3H), 4.95-5.10 (m, 2H), 5.75-5.90 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C[O:8][C:9](=O)[CH:10]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[CH2:11][CH:12]1[CH2:16][CH2:15][CH:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:13]1.C[O-].[Mg+2].C[O-].CO>>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13]2)[C:9]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:8])=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(S(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(OC3CCCCO3)C2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
2-Aminothiazole (259 mg, 2.58 mmol) and 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (1.06 g, 2.58 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 14.76 mL, 10.32 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/2 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (494 mg, 40%) as a yellow foam: mp 68–70° C. (foam to gel); FAB-HRMS m/e calcd for C23H30N2O5S2 (M+H)+ 479.1674, found 479.1666.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:22])([F:21])[C:14]1[N:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:20][C:17]2[CH:18]=[N:19][C:14]([C:13]([F:22])([F:12])[F:21])=[CH:15][CH:16]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 6-(trifluoromethyl)pyridin-3-ol
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[CH:22][C:21]=2[Cl:34])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45]Br.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[C:42]([Cl:41])[CH:43]=4)[CH:28]=3)=[CH:22][C:21]=2[Cl:34])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(CCCc2ccc(Sc3cccc(O)c3)cc2Cl)COC(C)(C)OC1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Sc3cccc(OCc4cccc(Cl)c4)c3)cc2Cl)COC(C)(C)OC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 34 (500 mg) in DMF (10 mL), potassium carbonate (500 mg) and m-chlorobenzyl bromide (0.16 mL) were added and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was then poured into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the desired product (520 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5](=[CH:9][C:10]=1[S:11](=[O:14])(=[O:13])[NH2:12])[C:6]([OH:8])=[O:7].O.[C:17](=O)([O-])[O-].[K+].[K+]>CO.S(=O)(=O)(O)O>[NH2:15][C:4]1[CH:3]=[C:2]([F:1])[C:10]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:9][C:5]=1[C:6]([O:8][CH3:17])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(F)c(S(N)(=O)=O)cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(S(N)(=O)=O)c(F)cc1N

Procedure:
A reaction flask, containing 7.2 g (0.0307 molecule) of 4-fluoro-5-sulphamylanthranilic acid (6) in 125 ml of methanol and 10 ml of concentrated sulphuric acid, was attached to a Soxhlet apparatus, containing molecular sieves 4A, immersed in methanol (25 ml). After 48 hours' reflux, the solution was poured into cold water (500 ml), containing 25 g of potassium carbonate. The solid, which separated out, was recovered on a filter and dried in vacuo at 80°; yield: 5.6 g (73.7%); m.p.: 209°-211°.