Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CC1(C)[O:15][C:14](=O)[CH2:13][C:12](=[O:17])[O:11]1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[CH2:13][C:12]([OH:17])=[O:11])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccc(Br)cc1
Product: O=C(O)CC(=O)Nc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
According to the general method described in Synth. Commun. 2010, 40, 732, a mixture of 4-bromoaniline (10.0 g, 58.1 mmol) and 2,2-dimethyl-1,3-dioxan-4,6-dione (8.40 g, 58.1 mmol) was heated at 80° C. for 1 hour and cooled to room temperature to provide 3-((4-bromophenyl)amino)-3-oxopropanoic acid as a solid. A stream of nitrogen gas was passed over the solid product to remove liquid acetone formed as a by-product. To this solid was added Eaton's reagent (40 mL) and heated at 70° C. for 12 hours and cooled to room temperature. To the resulting mixture was added water and stirred vigorously to provide a suspension which was filtered. The solid residue was washed with water and dried in air to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:20][NH:21][CH2:22][C@H:23]([OH:27])[CH2:24][S:25][CH3:26])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:28].CO>>[NH2:28][C:17]1[C:18]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[C:12]([CH2:20][NH:21][CH2:22][C@H:23]([OH:27])[CH2:24][S:25][CH3:26])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: N
Reactant: CSC[C@@H](O)CNCc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Solvent: CO
Product: CSC[C@@H](O)CNCc1cn(COCc2ccccc2)c2c(N)ncnc12
Temperature: 25 °C
Yield: 72 %

Procedure:
The product from Example 2.4 (0.124 g, 0.305 mmol) was stirred in a solution of 7M NH3-MeOH (25 ml) for 24 h in a sealed tube at 135° C. (oil bath). After cooling to rt the solvent was evaporated and the residue chromatographed on silica gel (CH2Cl2-7M NH3 in MeOH, 98:2) to give (S)-1-((4-amino-5-(benzyloxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-3-(methylthio)propan-2-ol (0.085 g, 72%) as a colourless gum. 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.47 (s, 1H), 7.28 (m, 5H), 5.66 (s, 2H), 4.58 (s, 2H), 3.97 (d, J=13.8 Hz, 1H), 3.91-3.83 (m, 2H), 2.84 (dd, J=12.1, 3.5 Hz, 1H), 2.62 (dd, J=12.1, 8.4 Hz, 1H), 2.56 (d, J=6.4 Hz, 2H), 2.09 (s, 3H). 13C NMR (CD3OD) δ 152.8, 151.6, 149.4, 137.7, 133.5, 129.5, 129.3, 129.2, 116.0, 114.3, 78.6, 71.4, 70.3, 54.6, 43.3, 40.4, 16.2. +ESMS Found 388.1813 (M+H)+ C19H26N5O2S requires 388.1807.
Reaction SMILES: CN(C)C(N1C[CH:9]=[C:8]([C:11]2[NH:58][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:38])[C:27]5[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=5[F:37])[C:20]=4[C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:40][SiH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=O.C([SiH2][O:65][C:66](C1C=CC=CC=1)(C1C=CC=CC=1)C1C(C2C3C=C(C4CCOCC=4)NC=3N=CN=2)=CC=CC=1N)(C)(C)C>>[C:42]([SiH2:41][O:40][C:39]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:20]1[C:19]([C:18]2[C:13]3[CH:12]=[C:11]([C:8]4[CH2:9][CH2:66][O:65][CH2:6][CH:7]=4)[NH:58][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=1[F:37])([CH3:44])([CH3:45])[CH3:43]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1c(N)cccc1-c1ncnc2[nH]c(C3=CCOCC3)cc12
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1c(NC(=O)c2ccc(C(C)(C)O)cc2F)cccc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Intermediate 14 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 13.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:35]5[CH2:34][CH2:33][NH:32][CH:31]([C:27]6[S:26][CH:30]=[CH:29][CH:28]=6)[CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: c1csc(C2CNCCN2)c1
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCNC(c5cccs5)C4)c(F)cc3cc2c1=O
Yield: 90.5 %

Procedure:
(RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 1-cyclopropyl-7,8-difluoro-3-ethoxycarbonyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.7 g) and (RS)-2-(2-thienyl)piperazine (1 g). (RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine (2.2 g) is obtained in the form of a yellow solid, m.p. 210°-212° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[C:6]#[N:7]
Reactant: Cc1cc(C#N)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(F)c(CBr)c1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of 4-fluoro-3-methylbenzonitrile (15.0 g, 111 mmol), in CCl4 (600 mL) was added N-bromosuccinimide (23.7 g, 133 mmol), and benzoyl peroxide (5.38 g, 22.2 mol). The mixture was irradiated with a sunlamp (250 W) to create a gentle reflux. After 0.5 hours of exposure the reaction was complete by TLC. The reaction mixture was cooled and filtered through celite. The filtrate was condensed in vacou to yield brown oil. The crude residue was purified via silica gel column chromatography (hexanes/ethyl acetate) to yield 17.7 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)n(C)c1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(C)c1=O
Temperature: 10 °C
Yield: 535.8 %

Procedure:
6-Amino-1-methyl-3-n-propyluracil (13.2 g, 7.3 mmol) was dissolved in 10-15 ml of acetic acid and the solution was warmed on a hot plate to 60°-70° C. Then, with stirring, a solution of sodium nitrite (5.3 g, 7.7 mmol) in 100 ml of water was added in 10 ml portions over 10 minutes. A brownish-purple precipitate formed. The reaction mixture was cooled to 10° C. and the precipitate was collected by vacuum filtration, washed with 10 ml of acetone, and air-dried to give 8.3 g (55%) of 6-amino-1-methyl-5-nitroso-3-n-propyluracil as a purple solid. 1H NMR (DMSO-d6 +D2O) δ0.90 (t, J=7 Hz, 3 H), 1.62 (sextet, J=7 Hz, 2 H), 3.26 (s, 3 H), 3.87 (t, J=7 Hz, 2 H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18](Br)=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9].[CH3:36]B(O)O.[F-].[Cs+]>O1CCOCC1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18]([CH3:36])=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: CB(O)O
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(Br)cc(C(F)(F)F)cc21
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(C)cc(C(F)(F)F)cc21
Temperature: 80 °C
Yield: 62.3 %

Procedure:
A mixture of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-bromo-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.0830 g, 0.144 mmol), methyl boronic acid (0.0260 g, 0.432 mmol) and cesium fluoride (0.0770 mg, 0.504 mmol) in dioxane (2.00 ml) was purged with nitrogen for 10 minutes. To it was added PdCl2(dppf) (0.0170 g) in one portion. The mixture was heated at 80° C. overnight. The solid was removed by filtration, washed with ethyl acetate (30.0 ml) and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (gradient eluent, 0-40% ethyl acetate in hexane) provided the titled compound (0.0460 g, 63%) as white solid. MS (ES+): 513 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1.O>[C:15]([O:19][C:20](=[O:21])[NH:22][CH2:26][CH2:25][CH2:24][C:23]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1)=[O:27])([CH3:18])([CH3:16])[CH3:17]
Reactant: CSc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cccc(C(=O)CCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
Cool a solution of 3-bromothioanisole (10.68 g, 52.6 mmol) in tetrahydrofuran (250 mL) to −78° C., and add n-butyllithium (2.5 M in hexanes, 25.9 mL, 64.8 mmol) over 25 min. Stir the reaction at −78° C. for 1.25 h, then slowly add a solution of 1-(tert-butoxycarbonyl)-2-pyrrolidinone (7.50 g, 40.5 mmol) in tetrahydrofuran (100 mL). Stir the reaction for 2 h at −78° C., then add saturated aqueous ammonium chloride (100 mL). Upon warming to room temperature, add water (200 mL), and extract the reaction with dichloromethane (3×300 mL). Combine the organic extracts and dry over magnesium sulfate, filter, and evaporate under reduced pressure to afford a crude mixture (14.91 g). Purify the crude mixture by flash chromatography (330 g RediSep silica gel column, gradient from 0:100 to 30:70 ethyl acetate:hexanes) to provide slightly impure product (10.34 g, 83%), which is used without further purification. MS (APCI+): 210 [C16H23NO3S—C5H8O2+H]+; 1H NMR (300 MHz, CDCl3): δ 7.81-7.82 (m, 1H), 7.67-7.71 (m, 1H), 7.41-7.45 (m, 1H), 7.34-7.39 (m, 1H), 4.64 (br s, 1H), 3.17-3.26 (m, 2H), 3.00 (t, J=7.1 Hz, 2H), 2.52 (s, 3H), 1.93 (quintet, J=7.0 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:33])[C:5]2[CH2:16][S:15][CH2:14][C@@H:13]([C:17]([O:19]C)=O)[NH:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9][O:8][C:7](=[O:30])[C:6]=2[C:31]=1[CH3:32].CO.[NH3:36]>>[C:17]([C@H:13]1[NH:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:9][O:8][C:7](=[O:30])[C:6]2[C:31]([CH3:32])=[C:2]([OH:1])[CH:3]=[C:4]([OH:33])[C:5]=2[CH2:16][S:15][CH2:14]1)(=[O:19])[NH2:36]
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reactant: N
Solvent: CO
Product: Cc1c(O)cc(O)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(N)=O)CSC2
Reaction time: 7 h

Procedure:
A solution of 291 mg of the product of Example 2 was dissolved in 6 ml of saturated methanolic ammonia which had been prepared by the introduction of dry ammonia into methanol at 10° C. The solution was kept at 20° C. for 7 hours, and then evaporated in vacuo. The residue was crystallized from ethyl acetate to yield 243 mg of tert-butyl (4R, 7S)-4-carbamoyl-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH:13]=O)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:18][N:17]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: NN
Reactant: O=Cc1c(Cl)c2ccc(Br)cc2[nH]c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2c2[nH]ncc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of 7-bromo-4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (8.0 g, 27.9 mmol) in 150 mL of DMF at 80° C. is added hydrazine hydrate (2 mL, 33.5 mmol) at 80° C. The reaction medium is stirred for 24 hours at 80° C. and then cooled to room temperature and filtered. The solid obtained is washed with diisopropyl ether and dried to give 5.3 g of 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one in the form of a pale yellow powder (yield: 72%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[CH2:16][C:17]([O:19]C)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:16][C:17]([OH:19])=[O:18])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1.16 g of 5-acetylsalicylic acid, methyl ester in 10 mL of N,N-dimethylformamide is added 1 g of chloroacetic acid, methyl ester and 1.2 g of potassium carbonate. After stirring this mixture at ambient temperature for 16 hours the reaction is filtered, diluted with ethyl acetate, and washed once with water and twice with brine. The ethyl acetate is dried with magnesium sulfate, filtered, and evaporated to give 5-acetyl-2-(carboxymethoxy)benzoic acid as a crude product. Crystallization from methanol at -15° C. gives 0.6 g of white crystals. 1H-NMR (CDCl3): 8.5 ppm (1H, d), 8.1 ppm (1H, dd), 6.9 ppm (1H, d), 4.8 ppm (2H, s), 4.0 ppm (3H, s), 3.8 ppm (3H, s), 2.6 ppm (3H, s).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([CH3:17])[N:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:1])=[O:15])[CH:11]=[C:10]([CH3:17])[N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Solvent: ClCCl
Product: COC(=O)c1cc(C)nc(Cl)c1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Oxalyl chloride (1.9 g, 15 mmol) was added to 2-chloro-6-methyl-pyridine-4-carboxylic acid (1.7 g, 10 mmol) in methylene chloride (30 ml) and the mixture stirred for 2 hours. The volatiles were removed by evaporation and methanol (20 ml) added to the residue. The mixture was stirred for 1 hour and the volatiles removed by evaporation to give methyl 2-chloro-6-methyl-pyridine-4-carboxylate (1.85 g, 100%) as an off-white solid. 1H NMR Spectrum: (CDCl3)2.55(s, 3H); 3.90(s, 3H); 7.55(s, 1H); 7.60(s, 1H); MS-ESI: 186 [MH]+
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)=[O:24])[CH2:6]1)(=[O:3])[CH3:2]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[O:11])[CH2:27][CH2:26]2)=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 2 h
Yield: 166.2 %

Procedure:
A solution of 1.10 g of N-nitrobenzyl chloroformate in 10 ml of methylene chloride was added, whilst ice-cooling, to a solution of 1.63 g of (2S,4S)-4-acetylthio-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine and 0.62 g of 4-dimethylaminopyridine in 15 ml of methylene chloride and the resulting mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was diluted with 100 ml of ethyl acetate, and the dilute solution was washed, in turn, with 100 ml of an aqueous solution of sodium hydrogencarbonate, with 100 ml of water and with 100 ml of an aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol ranging from 30:1 to 25:1 by volume as the eluent to give 1.86 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the compound thus obtained were identical with those of the compound prepared as described in step 90(b)(ii) above.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:24]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([C:17]([O:19]CC)=[O:18])=[CH:15][N:16]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1.O>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:23]1[CH:22]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=2[Cl:1])[CH:24]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=1)=[O:10]
Reactant: CCOC(=O)c1cnc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ncc(C(=O)O)s1)c1cc(OCc2ccccc2Cl)cc(OCc2ccccc2Cl)c1

Procedure:
A solution of ethyl 2-[3,5-di-(2-chlorobenzyloxy)benzoyl]aminothiazole-5-carboxylate (158 mg, 0.28 mmol) in THF (2 ml) was treated with sodium hydroxide solution (0.57 ml of 2M, 1.4 mmol), and the reaction stirred at 40-50 deg C., until complete hydrolysis was achieved (with tlc monitoring, approximate reaction time 2 hrs). The resulting solution was cooled, diluted with water (5 ml) and acidified to pH1 using c.HCl. The precipitate thus formed was filtered off, washed (water) and dried to give the title compound as a colourless solid, 130 mg, 1H NMR δ (d6-DMSO): 5.25 (4H, s); 7.0 (1H, s); 7.4 (6H, m); 7.5 (2H, m); 7.6 (2H, m); 8.2 (1H, d).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:40][CH2:41][C:42]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[O:43])=[CH:15][N:16]3[CH2:19][C:20]3[CH:37]=[CH:36][C:23]([C:24](NS(C4C=CC=CC=4)(=O)=O)=[O:25])=[CH:22][C:21]=3[O:38][CH3:39])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.BrCC1C=CC(C(OC(C)(C)C)=[O:57])=CC=1OC.Cl>CN(C)C1C=CN=CC=1.N1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:40][CH2:41][C:42]([N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[O:43])=[CH:15][N:16]3[CH2:19][C:20]3[CH:37]=[CH:36][C:23]([C:24]([OH:25])=[O:57])=[CH:22][C:21]=3[O:38][CH3:39])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1COCCN1
Product: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Yield: 41 %

Procedure:
The starting indole was obtained as follows: A solution of 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl)]-3-methoxybenzoic acid (0.68g)(prepared as described in Example 1, parts (a) through (i)) and 4-(dimethylamino)pyridine (0.17 g) in morpholine (4 ml) was heated at 80° for 48 hours under a nitrogen atmosphere. The reaction was diluted with water and acidified with 10% (v/v) hydrochloric acid. The resultant precipitate was collected by filtration and washed with water. The product was purified by recrystallization from ethyl acetate to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(morpholinocarbonyl)ethyl]indol-1-ylmethyl]-3-methoxybenzoic acid as a white powder (0.31 g, 41%); partial NMR (80 MHz, CDCl3) 1.2-1.8(m, 9H, cyclopentyl), 2.70(dd, 2H, CH2NH), 3.15(t, 2H, COCH2), 3.2-3.7(m, 8H, morpholino), 3.92(s, 3H, OCH3), 5.35(s, 2H, ArCH2), 6.58(t, 1H, NH), 7.17(d, 1H), 7.9(s, 1H, H7 -indole).
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:13])=[O:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH2:52][C@@H:53]([CH:69]([CH3:71])[CH3:70])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=2)[C@H:50]([CH2:72][C@H:73]([C:77](O)=[O:78])[CH:74]([CH3:76])[CH3:75])[O:49][C:48]1([CH3:81])[CH3:80])=[O:46])([CH3:43])([CH3:42])[CH3:41]>CN(C)C=O>[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH2:52][C@@H:53]([CH:69]([CH3:71])[CH3:70])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=2)[C@H:50]([CH2:72][C@H:73]([C:77](=[O:78])[NH:9][C:10]([C:11](=[O:12])[NH2:13])([CH3:15])[CH3:14])[CH:74]([CH3:75])[CH3:76])[O:49][C:48]1([CH3:80])[CH3:81])=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Reactant: CC(C)(N)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Temperature: 40 °C
Reaction time: 192 h

Procedure:
106 μl of 4-methyl-morpholine, 66 mg of 2-aminoisobutyric acid amide hydrochloride and 91 mg of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) are added in succession to 119 mg of 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124c) in 8 ml of dimethylformamide. The reaction mixture is stirred for 8 days at 40° C. The mixture is concentrated by evaporation and the residue is partitioned between ethyl acetate and saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by means of FC (60 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.30.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]([O:32][CH3:33])=[O:31])=[O:15])[CH3:14]
Reactant: C=CC(=O)OC
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)CCC(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.34 ml, 0.0024 mole), trimethyl silylchloride (0.31 ml, 0.0024 mole) and methyl acrylate (0.22 ml, 0.0024 mole). The reaction mixture was stirred at room temperature for 4 hours and then stirred at reflux for 23 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 5% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water and 5% NaHCO3, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a clear liquid solid (0.6 g). The crude product was purified through column chromatography (1:1 hexane/acetone eluting solvent system) to yield 0.19 g oil.