Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[OH:10][C:11]1[CH:21]=[CH:20][CH:19]=[C:13]2[C:14]([O:16][C:17](=[O:18])[C:12]=12)=[O:15].[CH3:22][O:23][CH2:24]Cl>ClC(Cl)C>[CH3:22][O:23][CH2:24][O:10][C:11]1[CH:21]=[CH:20][CH:19]=[C:13]2[C:14]([O:16][C:17](=[O:18])[C:12]=12)=[O:15]
Reactant: COCCl
Reactant: O=C1OC(=O)c2c(O)cccc21
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc2c1C(=O)OC2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
N,N-Diisopropylethylamine (4.39 g, 34.0 mmol) was added to a solution of 3-hydroxyphthalic anhydride (5.0 g, 30.5 mmol) in dichloroethane (60 ml), then chloromethyl methyl ether (2.57 g, 32.0 mmol) was dropped thereinto under cooling with ice water and the mixture was returned to room temperature and stirred for 1 hour. Then N,N-diisopropylethylamine (2.20 g, 17.0 mmol) and chloromethyl methyl ether (1.28 g, 16.0 mmol) were further added thereto followed by stirring for 1 hour. After the reaction, the solvent was evaporated and the residue was diluted with water followed by extracting with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom to provide 6.3 g (yield 99%) of 3-methoxymethyloxyphthalic anhydride as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:8][C:6]=2[N:7]=1.[CH3:28][N:29]([CH:31](OC)OC)[CH3:30]>>[C:24]([NH:23][C:21](=[O:22])[NH:20][C:9]1[C:10]([C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([N:1]=[CH:28][N:29]([CH3:31])[CH3:30])=[N:7][C:6]=2[N:8]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl
Product: CN(C)C=Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1

Procedure:
1-[2-Amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-yl]-3-tert-butylurea from Example 3 was reacted with DMF dimethyl acetal for 13.5 hours as described in Example 78. Workup as described above, followed by purification on flash silica gel chromatography eluting sequentially with 100:0, 3:1, 1:1, and 0:100 dichloromethane:ethyl acetate gave a solid that was triturated in 2-propanol to afford the title compound N'-[7-(3-tert-butylureido)-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-2-yl]-N,N-dimethylformamidine, mp 190°-193° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH3:38]
Reactant: CCNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-ethyl-benzenesulfonamide [CAS 56445-08-0] according to general procedure II. Light yellow solid. MS (ISP) 538.1 [(M−H)−]; mp 259° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.Cl.[C:30]12([CH2:40][CH2:41][NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:30]12([CH2:40][CH2:41][N:42]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:37][CH:36]3[CH2:35][CH:34]([CH2:33][CH:32]([CH2:38]3)[CH2:31]1)[CH2:39]2
Reactant: CCCCCNCCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCNC(=O)OC(C)(C)C
Temperature: -15 °C
Yield: 85.2 %

Procedure:
3-(t-Butoxycarbonylamino)propionic acid (1.0 g, 5.3 mmol) was dissolved in anhydrous tetrahydrofuran (15 ml), and N-methylmorpholine (0.6 ml, 5.5 mmol) was added to the solution. The mixture was stirred at −15° C., and isobutyl chlorocarbonate (0.7 ml, 5.4 mmol) was added thereto. Then, a solution of a free base of 2-(1-adamantyl)-N-pentylethylamine hydrochloride (Intermediate No. 1-1) (1.5 g, 5.3 mmol) in anhydrous tetrahydrofuran (15 ml) was added thereto at −18° C. The whole was stirred at 0° C. for 1.5 hours, ethyl acetate (100 ml) and a saturated aqueous sodium hydrogencarbonate solution (100 ml) were added to the reaction mixture, and the reaction mixture was distributed. The organic layer was washed with a 10% aqueous citric acid solution (100 ml), water (100 ml) and a saturated aqueous sodium chloride solution (100 ml) successively and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 1.9 g (85%) of 3-(t-butoxycarbonylamino)propionic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide as an oily matter.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:25]=[C:26]([NH:31]C(=O)OC(C)(C)C)[C:27]([OH:30])=[N:28][CH:29]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl.CCCCCC>[NH2:31][C:26]1[C:27]([OH:30])=[N:28][CH:29]=[C:24]([CH:25]=1)[C:22]([NH:21][C@@H:13]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[C:2]([F:1])[CH:3]=1)[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cnc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cnc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of ((S)-tert-butyl (5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-hydroxypyridin-3-yl)carbamate (600 mg, 0.0011 mol), in DCM (6 mL) was added TFA (1.2 mL, 0.143 mol, Aldrich). The resulting mixture was then stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 30% EtOAc in hexane), the reaction mixture was quenched with sat'd NaHCO3 solution (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.78 (s., 1H), 9.00 (d, J=7.8 Hz, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.79 (dd, J=1.2, 9.9 Hz, 1H), 7.60-7.43 (m, 3H), 7.35 (d, 8.7 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.18 (br.s., 2H). MS (ESI, positive ion) m/z: 441.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=2[CH:8]=[CH:7][N:6]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][C:26]=1[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][C:26]=1[C:27]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[CH:7][N:6]=[C:5]2[O:4][C:3]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:2]=1[F:1])=[O:28]
Reactant: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)nccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cc(C(F)(F)F)ccc4F)nccc23)c1
Yield: 25.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(2-fluoro-5-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-36, 80 mg, 0.24 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 134 mg, 0.49 mmol), oxalyl chloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) in CH2Cl2 (5 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.32 (d, 1H), 8.11 (t, 1H), 8.09 (d, 1H), 8.00-7.96 (m, 2H), 7.75-7.69 (m, 4H), 7.55 (m, 2H), 7.38 (d, 1H), 4.32 (d, J=5.4 Hz, 2H), 1.14 (s, 9H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14][CH:13]=1.[F:27][C:28]1[CH:34]=[C:33]([I:35])[CH:32]=[CH:31][C:29]=1[NH2:30]>C1COCC1.CCOC(C)=O>[F:27][C:28]1[CH:34]=[C:33]([I:35])[CH:32]=[CH:31][C:29]=1[NH:30][C:12]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14][CH:13]=1
Reactant: O=C(O)c1cc(-c2ccccc2)ncc1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)ncc1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Lithium bis(trimethylsilyl)amide (2.8 ml, 1.0 M in THF, 2.76 mmol) was added to a suspension of 5-fluoro-2-phenylisonicotinic acid (500 mg, 2.30 mmol) in THF (10 ml) at −78° C. The dark colored suspension was stirred for 30 min. In another flask, 2-fluoro-4-iodoaniline (709.30 mg, 2.99 mmol, 1.30 eq) was dissolved in (15 ml) THF and cooled to −78° C. To this solution lithium bis(trimethylsilyl)amide (5 ml, 1.00 M, 5.06 mmol, 2.20 eq) was added and the mixture was stirred for 1 h. The reaction mixture became very viscous. To this, the homogeneous solution of acid-LiHMDS mixture was added via syringe. The mixture was warmed to room temperature and stirred overnight. Diluted with EtOAc (300 ml), washed with dilute HCl (20 ml), water (20 ml), and then dried and concentrated. Purified on Flashmaster using 100 g cartridge to obtain 565 mg of 5-[(2-fluoro-4-iodophenyl)amino]-2-phenylisonicotinic acid. LC/MS: [8.59 min; 435 (M+1)]
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][C@@:7]1([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1O)([O-:3])=[O:2].N1C=CC=CC=1.C(N(CC)CC)C>O>[N+:1]([C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][C@@:7]1([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:8]1)([O-:3])=[O:2]
Reactant: Nc1ncnc2c1ncn2[C@]1(Cc2ccccc2[N+](=O)[O-])O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: Nc1ncnc2c1ncn2[C@@]1(Cc2ccccc2[N+](=O)[O-])C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.5 %

Procedure:
To 2'-deoxy-N -bis-ortho-nitrobenzyladenosine (200 mg, 0.518 mmol) was added anhydrous pyridine (10 ml) and evaporated to dryness. Pyridine (10 ml) was added followed by 4-4'-dimethoxytrityl chloride (900 mg, 2.3 mmol, 4.5 equiv.) and triethylamine (280 mg, 2.76 mmol, 4.0 equiv.) and stirred at room temperature under an argon atmosphere for 5 hours. Water (0.5 ml) was added and stirred for 20 minutes. The mixture was partitioned between ether and water (20 ml each) and the aqueous phase was re-extracted with ether (20 ml). The extracts were combined and washed with water (20 ml) and dried over anhydrous sodium sulfate, filtered and evaporated. The material was purified by chromatography on silica gel (4 g, using 0.7-2.5% methanol in methylene chloride) to yield 5'-O-DMT- N6 -bis-ortho-nitrobenzyl-2'-deoxyadenosine, (121 mg, 33%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: Cc1cc(Oc2ncccn2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2ncccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Yield: 38.6 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)thiazol-2-amine (6-3, 0.23 g, 0.77 mmol) in THF (3.9 mL) was added triethylamine (0.23 g, 2.30 mmol) followed by isonicotinoyl chloride hydrochloride (0.27 g, 1.52 mmol). The reaction mixture was heated at 60° C. overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was recrystallized in MeOH to give N-{4-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)thiazol-2-yl}isonicotinamide (6, 0.12 g) as yellow solids in 38% yield: 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J=6.0 Hz, 2 H), 8.58 (d, J=4.5 Hz, 2 H), 7.65 (d, J=6.0 Hz, 2 H), 7.04 (t, J=4.8 Hz, 1 H), 6.83 (s, 1 H), 6.70 (s, 2 H), 3.47 (s, 3 H), 1.97 (s, 6 H). ESI-MS: m/z 403.8 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=[O:28])[N:15]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[C:14](=[O:23])[C:13]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:12]12>C(O)CCC>[C:14]1(=[O:23])[N:15]([CH:16]2[CH2:17][C:18]3[C:7]4[C:6](=[CH:5][CH:4]=[C:3]([Br:2])[CH:8]=4)[NH:9][C:19]=3[CH2:20][CH2:21]2)[C:11](=[O:28])[C:12]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:13]12
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCCCO
Product: O=C1c2ccccc2C(=O)N1C1CCc2[nH]c3ccc(Br)cc3c2C1
Yield: 104.1 %

Procedure:
Reaction of 4-bromophenylhydrazine hydrochloride (4.0 g, 18.1 mmol) with 4-phthalimido-cyclohexanone (4.39 g, 18.1 mmol) in refluxing n-butanol for 20 min, followed by cooling, filtration, and evaporation of the filtrate to dryness yielded 3-phthalimido-6-bromo-1,2,3,4-tetrahydrocarbazole as an orange solid (7.45 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:7]2.[C:21]([Li])(C)(C)C.CN(C)C=O>CCOCC>[CH3:21][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:7]2
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)COS(=O)(=O)c1ccc2c(Br)cccc2c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc2cc(S(=O)(=O)OCC(C)(C)C)ccc12
Reaction time: 1 h

Procedure:
To a cooled (-80° C.) solution of neopentyl 5-bromonaphthalene-2-sulfonate (300 mg; 0.84 mmol) in anhydrous ether (12 mL) is added tert-butyllithium (1.7M in ether) (1 mL; 1.7 mmol), immediately followed by a solution of dimethylformamide (125 mg; 1.7 mmol) in ether (2 mL). The external cooling bath is removed and stirring is allowed to proceed for 1 hour. The reaction mixture is quenched with water (10 mL), the two solution phases are separated and the aqueous phase is extracted with ether (2×10 mL). The combined organic phase is dried (MgSO4), filtered and concentrated under reduced pressure to afford crude neopentyl 5-methylnaphthalene-2-sulfonate.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([O:14]C)=[O:13])[CH2:4]1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C@H:3]1[C@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@@H:5]([C:12]([OH:14])=[O:13])[CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CO[C@@H]1C[C@H](C(=O)O)C[C@H]1O[N+](=O)[O-]
Temperature: 10 °C
Yield: 92 %

Procedure:
A solution of (+)-methyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate (0.658 g, 3 mmol) in methanol (12 ml) was cooled to 0° C. To this was added 4N KOH (1.500 ml, 6.00 mmol) dropwise over 10 minutes and the solution was stirred and allowed to warm to 10° C. over 3 h. The reaction mixture was neutralized to pH 7 by addition of 0.5 mL concentrated HCl and then the solution was concentrated under vacuum to remove methanol. To the residue was added 10 ml CHCl3 and 2 mL water and the pH was adjusted to 3-4 by addition of 2M HCl. The layers were separated and the aqueous layer was washed with two 15 mL portions of CHCl3. The combined organic layers were washed with brine and dryed over Na2SO4 to give the title compound (0.566 g, 2.76 mmol, 92% yield) as a colorless oil; 1H NMR (500 MHz, CDCl3) δ 2.08-2.18 (m, 2H), 2.32-2.4 (m, 1H), 2.52-2.58 (m, 1H), 3.05 (quintet, J=8.3 Hz, 1H), 3.40 (d, J=0.7 Hz, 3H), 5.31 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]([CH3:39])=[C:33]([CH2:35][CH2:36][CH2:37]O)[N:34]=2)=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:37][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[O:31][C:32]=2[CH3:39])=[CH:9][CH:8]=1)[CH3:2]
Reactant: COc1ccc(-c2nc(CCCO)c(C)o2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCCc2nc(-c3ccc(OC)cc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propanol (example 42 e]) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:9]2[N:8]3[CH:10]=[CH:11][CH:12]=[C:7]3/[C:6](=[N:13]/[O:14][CH2:15][CH2:16]Br)/[C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C)C=O>O>[CH3:1][C:2]1[C:9]2[N:8]3[CH:10]=[CH:11][CH:12]=[C:7]3/[C:6](=[N:13]/[O:14][CH2:15][CH2:16][NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)/[C:5]=2[S:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2c1-n1cccc1/C2=N/OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2c1-n1cccc1/C2=N/OCCNCc1ccccc1
Yield: 64.8 %

Procedure:
Add 1 g (3.2 mmol) of (Z)-3-methyl-8-[(2-bromo-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole, 0.53 g (3.8 mmol) of potassium carbonate and 0.51 g (4.8 mmol) of benzylamine in succession to 20 ml of N,N-dimethylformamide. The reaction mixture is heated at reflux for 3 hours then, after cooling, is poured into 100 ml of water and extracted with diethyl ether. The ethereal phase is washed with water, dried over magnesium sulfate, rendered colourless with animal charcoal and then concentrated under reduced pressure to yield 0.7 g of the title product in the form of an oil (base).
Reaction SMILES: C(O[C:5]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[S:19][CH:20]=[CH:21][C:11]=3[C:10]=2[C:9]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])=[CH:24][CH:23]=1)=[O:6])(C)C.[C:38](OC(=O)C)(=O)C>>[C:5]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[S:19][CH:20]=[CH:21][C:11]=3[C:10]=2[C:9]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:31]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:37])[CH3:29])=[CH:24][CH:23]=1)(=[O:6])[CH3:38]
Reactant: CC(C)OC(=O)Oc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Yield: 62.7 %

Procedure:
Following Procedure Preparing tert-butyl 1-(4-(8-(isopropoxycarbonyloxy)-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate, (44 mg, 0.10 mmol) was reacted with acetic anhydride (11 μL, 0.12 mmol) to afford the desired product (30 mg, 63%) as a solid: ESI MS m/z 479 [C26H26N2O5S+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH3:32])(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccccc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=575.7)=82%.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[CH:10]([C:13]([O:15]C)=[O:14])[CH2:11][O:12][C:8]=3[CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.O[Li].O>CO.C1COCC1.O>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[CH:10]([C:13]([OH:15])=[O:14])[CH2:11][O:12][C:8]=3[CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)C1COc2cc(-n3cnnn3)ccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1COc2cc(-n3cnnn3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(1H-tetrazol-1-yl)-2,3-dihydro-1-benzofuran-3-carboxylate (3.3 g, 13.6 mmol) in 100 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (2.84 g, 67.5 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and the residue was added 50 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was re-crystallized from DCM to give 6-(1H-tetrazol-1-yl)-2,3-dihydro-1-benzofuran-3-carboxylic acid. 1H-NMR (300 MHz, DMSO) δ ppm 7.58 (d, J=7.8 Hz, 1H), 7.32-7.50 (m, 2H), 4.71-4.92 (m, 2H), 4.45-4.55 (m, 1H); MS m/z 233 (M+1)+.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:27]([C:15]1[CH:14]=[C:13]([CH2:12][CH:11]([NH2:10])[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:18]=[CH:17][C:16]=1[OH:19])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc(CC(CS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(CC(N)CS(C)(=O)=O)ccc1O
Yield: 100.1 %

Procedure:
A mixture of 2-(4-benzyloxy-3-t-butylphenyl)-1-methanesulfonylmethylethylcarbamic acid benzyl ester (1.0 g, 1.96 mmol) and 20% palladium hydroxide/carbon (0.08 g) in methanol (16 ml) was stirred at room temperature in a hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=100:10:1), giving the titled compound (0.56 g, 99%).