Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH2:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=O.[CH2:23]1[CH2:33]CN2C(=NCCC2)C[CH2:24]1.ICCC>CN1C(=O)CCC1.C(OCC)(=O)C>[C:10]([C:5]1[C:6]([C:8]#[N:9])=[CH:7][C:2]2[N:1]([CH2:24][CH2:23][CH3:33])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][C:3]=2[CH:4]=1)#[N:11]
Reactant: N#Cc1cc(N)c(N)cc1C#N
Reactant: O=Cc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Agent: O=O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCI
Product: CCCn1c(-c2ccccc2)nc2cc(C#N)c(C#N)cc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A 25 mL round-bottom flask was charged with 3 (316 mg, 2.00 mmol), NMP (10 mL), benzaldehyde, (202 μL, 2.00 mmol), and a magnetic stirring bar. The flask was fitted with a Hickman still, placed in an oil bath heated to 120° C., and stirred for 1 h. Then FeCl3.6H2O (27 mg, 0.10 mmol) was added to the reaction vessel and oxygen was bubbled through the mixture as it was heated and stirred for an additional 20 h. The reaction mixture was then removed from heat and added to ethyl acetate. The ethyl acetate solution was washed three times with water, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue (458 mg, 1.88 mmol) was dissolved in NMP (2 mL) and heated to 80° C. Then DBU (280 μL, 1.88 mmol) was added and the mixture was stirred for 2 min, and iodopropane (183 μL, 1.88 mmol) was added. After 20 min, the mixture was treated with a second round of DBU and iodopropane, and after an additional 20 min, a third round of reagents was added. After a final 20 min of heating, the mixture was transferred to ethyl acetate and washed three times with water, followed by brine. After drying the organic layer over Na2SO4, the mixture was filtered, concentrated to dryness, and chromatographed (silica, CH2Cl2, 3% ethyl acetate, 1% isopropanol), yielding an off-white solid (253 mg, 44%): mp 183-185° C.; 1H NMR (CDCl3) δ 0.90 (t, J=7.6 Hz, 2H), 1.81-1.92 (m, 2H), 4.29 (t, J=7.6 Hz, 2H), 7.56-7.62 (m, 3H), 7.70-7.73 (m, 2H), 7.89 (s, 1H), 8.20 (s, 1H); 13C NMR (CDCl3) δ 11.4, 23.5, 47.3, 108.7, 109.0, 116.7, 116.8, 116.9, 126.6, 128.8, 129.5, 129.5, 131.4, 137.8, 145.4, 159.5; FAB-MS obsd 287.1302, calcd 287.1297 [(M+H)+; M=C18H14N4].
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C(O)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=1>C(#N)C.O>[Cl:1][CH2:38][C:36]1[CH:35]=[CH:34][N:33]=[C:32]([F:31])[CH:37]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1cc(CCl)ccn1
Temperature: 25 °C

Procedure:
N-Chlorosuccinimide (8.8 g, 66 mmol), acetic acid (0.15 mL) and benzoyl peroxide (220 mg, 0.91 mmol) were added to a solution of 2-fluoro-4-picoline (5.0 g, 45 mmol) in acetonitrile (25 mL) at room temperature, and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added thereto, and then the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (200 mL) and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, hexane/ethyl acetate (1:1) was added to the resulting residue, and then the insoluble matter was filtered out. The filtrate was evaporated under reduced pressure to give 6.5 g of the title reference compound as a crude product.
Reaction SMILES: [C:1]1(=[O:15])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:3]2[C:4]3[C:5](=[C:6]4[C:11](=[CH:12][CH:13]=3)[N:10]=[CH:9][CH:8]=[CH:7]4)[C:1](=[O:15])[C:2]2=[O:14])=[CH:22][CH:21]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C1Nc2ccc3ncccc3c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)C(=O)c3c2ccc2ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a stirred solution of 1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione (Bramson, H. N. et al. J. Med. Chem. 2001, 44 (25):4339-4358) (0.15 g, 0.76 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 0.04 g, 0.98 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 1 h and 4-methoxybenzyl bromide (0.16 mL, 1.1 mmol) was added. The mixture was stirred at ambient temperature for 16 h and was diluted with water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with a 50% to 65% gradient of ethyl acetate in hexanes to afford 3-(4-methoxybenzyl)-1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione (0.20 g, 82%) as a red solid: MS (ES+) m/z 319.0 (M+1).
Reaction SMILES: [OH-].[K+].NC1C2[C:16](=[O:18])C3C(=CC=CC=3)C(=O)C=2C(NS(C2C=CC=CC=2)(=O)=O)=CC=1S(O)(=O)=O.[NH2:34][C:35]1[C:48]2[C:47](=[O:49])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:50])[C:39]=2[C:38]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)(=[O:54])=[O:53])=[CH:37][C:36]=1S(O)(=O)=O.[NH2:66][C:67]1[C:80]2[C:79](=[O:81])[C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[C:72](=[O:82])[C:71]=2[C:70]([NH:83][S:84]([C:87]2[C:88](C)=[CH:89][CH:90]=[CH:91][CH:92]=2)(=[O:86])=[O:85])=[CH:69][C:68]=1[O:94][CH3:95].NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(NS(C2C=CC=CC=2)(=O)=O)=CC=1OC>CO>[NH2:34][C:35]1[C:48]2[C:47](=[O:49])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:50])[C:39]=2[C:38]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)(=[O:54])=[O:53])=[CH:37][C:36]=1[O:18][CH3:16].[NH2:66][C:67]1[C:80]2[C:79](=[O:81])[C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[C:72](=[O:82])[C:71]=2[C:70]([NH:83][S:84]([C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)(=[O:86])=[O:85])=[CH:69][C:68]=1[O:94][CH3:95]
Reactant: Nc1c(S(=O)(=O)O)cc(NS(=O)(=O)c2ccccc2)c2c1C(=O)c1ccccc1C2=O
Reactant: COc1cc(NS(=O)(=O)c2ccccc2C)c2c(c1N)C(=O)c1ccccc1C2=O
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(S(=O)(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)cc1
Agent: COc1cc(NS(=O)(=O)c2ccccc2)c2c(c1N)C(=O)c1ccccc1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NS(=O)(=O)c2ccc(C)cc2)c2c(c1N)C(=O)c1ccccc1C2=O

Procedure:
To a homogenous mixture of 225 g. potassium hydroxide in 450 g. methanol cooled to 60°-70° C is added 87 g. of the mixed potassium salts of 1-amino-4-benzenesulfonamido-2-anthraquinonesulfonic acid and 1-amino-4-p-toluenesulfonamido- 2-anthraquinone sulfonic acid. After holding this mixture for about 2 hours at 75°-80° C, the reaction mass is diluted with 750 g. water, filtered at less than 40° C, washed free of alkali with warm and then hot water and the product recovered as a red presscake. There is obtained 65 g. of product calculated on a dry basis, consisting of a mixture which is approximately 48% 1-amino-2-methoxy-4-toluenesulfonamidoanthraquinone and approximately 52% 1-amino-2-methoxy-4-benzenesulfonamidoanthraquinone. The mixture when dispersed in the usual manner dyes polyester textile materials, such as Dacron, red shades which are considerably stronger and brighter than comparable dyeing using dispersions of either of the individual components.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(C2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Solvent: CO
Product: COC1=C(C)C(c2ccc(C3CCCCC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(4-cyclohexylphenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.900 g, 2.32 mmol, 1 eq) and MeOH (10 ml); yield: 0.200 g (21.4%); MS m/z: 402.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.4 (b, 1H), 8.32 (s, 1H), 7.71 (s, 1H), 7.46-7.44 (m, 1H), 7.34 (m, 1H), 7.16-7.11 (m, 4H), 5.77 (s, 1H), 3.93 (s, 3H), 2.39 (m, 1H), 1.79-1.60 (m, 8H), 1.40-1.20 (m, 6H); HPLC (METHOD [A]): rt 15.68 min (96.92%)
Reaction SMILES: [F:1][C:2]([F:30])([CH2:25][C:26]([F:29])([F:28])[F:27])[C:3]([F:24])([F:23])[O:4][CH2:5][C:6]1([CH2:10][O:11][C:12]([F:22])([F:21])[C:13]([F:20])([F:19])[CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][O:8][CH2:7]1.[BrH:31]>>[Br:31][CH2:7][C:6]([CH2:10][O:11][C:12]([F:22])([F:21])[C:13]([F:20])([F:19])[CH2:14][C:15]([F:18])([F:17])[F:16])([CH2:5][O:4][C:3]([F:24])([F:23])[C:2]([F:30])([F:1])[CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:9][OH:8]
Reactant: Br
Reactant: FC(F)(F)CC(F)(F)C(F)(F)OCC1(COC(F)(F)C(F)(F)CC(F)(F)F)COC1
Product: OCC(CBr)(COC(F)(F)C(F)(F)CC(F)(F)F)COC(F)(F)C(F)(F)CC(F)(F)F
Yield: 89.1 %

Procedure:
In a manner similar to that described above, 3,3-bis(heptafluorobutoxymethyl)oxetane (250.0 g, 0.52 mole) was reacted with 48% HBr (131.7 g, 0.78 mole) to give 260.9 g (89.1%) of 3-bromo-2,2-bis(heptafluorobutoxymethyl)-1-propanol, a clear oil: 1H NMR (CDCl3) 3.49 (s, 2H), 3.65 (s, 4H), 3.69 (s, 2H), and 3.95 (t, J=13.3 Hz, 2H); Anal. Calcd for C13H13BrF14O3 : C, 27.72; H, 2.33; Br, 14.19; Found: C, 27.73; H, 2.27; Br, 14.09.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:12]#[CH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[CH3:15].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([C:13]#[C:12][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][C:8]=2[CH3:11])=[CH:22][CH:21]=1)[CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(I)cc1
Reactant: C#Cc1cc(C(C)(C)C)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C#Cc2cc(C(C)(C)C)ccc2C)cc1

Procedure:
Following General Procedure B and using 4-tert-butyl-2-ethynyl-1-methyl-benzene (Intermediate 110, 0.08 g, 0.47 mmol), ethyl-4-iodocinnamate (0.12 g, 0.4 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 2-4% ethyl acetate in hexane as the eluent, the title compound was obtained (0.09 g, 55%).
Reaction SMILES: C(OC(=O)[NH:7][S:8]([O:11][CH2:12][C@@H:13]1[C@@H:20]2[C@@H:16]([O:17]C(C)(C)[O:19]2)[CH:15]([NH:23][C:24]2[N:29]3[N:30]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([S:39][C:40]([F:43])([F:42])[F:41])[CH:34]=4)[CH:32]=[C:28]3[N:27]=[CH:26][CH:25]=2)[CH2:14]1)(=[O:10])=[O:9])(C)(C)C.P(=O)(O)(O)O.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[S:8](=[O:10])(=[O:9])([O:11][CH2:12][C@H:13]1[CH2:14][C@@H:15]([NH:23][C:24]2[N:29]3[N:30]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([S:39][C:40]([F:43])([F:42])[F:41])[CH:34]=4)[CH:32]=[C:28]3[N:27]=[CH:26][CH:25]=2)[C@H:16]([OH:17])[C@@H:20]1[OH:19])[NH2:7]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@H]1CC(Nc2ccnc3cc(-c4cccc(SC(F)(F)F)c4)nn23)[C@@H]2OC(C)(C)O[C@H]12
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2ccnc3cc(-c4cccc(SC(F)(F)F)c4)nn23)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl-[({(3aR,4R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methoxy)sulfonyl]carbamate (4.0 g) in acetonitrile (20.0 mL) at 0° C. was added phosphoric acid (20.0 mL) while maintaining the temperature below 10° C. This mixture was warmed to ambient temperature and stirred for 4 hours. At this time HPLC analysis showed that <1% starting material or reaction intermediates remained. To the reaction was added ethyl acetate (20 mL) and water (20 mL). After this addition was complete saturated Na2CO3 (80.0 mL) was added until the pH was between 6-7. After stirring for 10 minutes the phases were separated and the aqueous layer was back extracted with ethyl acetate (20 mL). The organic layers were combined and dried with Na2SO4. The organic layer was then concentrated to 4 vol of ethyl acetate. The solution started to precipitate within 5 minutes. This mixture was stirred for 16 hours. The resulting white solids were collected using a filter over 5 minutes. The solid was dried in a vacuum oven under full vacuum overnight (35° C., 16 hours). This yielded (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate anhydrous Form 1. (2.85 g, 84%). XRPD data is shown in FIG. 1; DSC data is shown in FIG. 2; TGA is shown in FIG. 3; Raman data is shown in FIGS. 4, 5A, 6A and 7A.
Reaction SMILES: ClC1C(O[C:9](=[O:29])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=[O:28])[CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])[NH2:38].Cl.C(N1CCCCC1)C>CN(C)C=O>[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])[NH:38][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(NCC(=O)N1CCC[C@H]1C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)OCc1ccccc1
Agent: CCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of benzyloxycarbonylglycyl-proline pentachlorophenyl ester (5.55 g, 10 mmoles) in dimethylformamide (30 ml) was added alanine methyl ester liberated from its hydrochloride (1.4 g, 10 mmoles) with N-ethylpiperidine (1.4 ml). After 5 hours of a stirring and 12 hours of standing at room temperature the solution was evaporated, the residue was taken into ethyl acetate and the organic phase was washed successively with 1M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from ethyl acetate-petroleum ether to give 1.95 g (50%) of the title product, m.p. 103° to 106° C. An analytical sample was recrystallized similarly, m.p. 105° to 108° C. [α]D20 -100.1° (c 0.2, MeOH).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>O1CCCC1>[C:12]([O:11][C:9]([NH:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:7][O:8][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:10])([CH3:14])([CH3:13])[CH3:15]
Reactant: CCCC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[C@@H](COCC(=O)OCC)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 55 %

Procedure:
To as stirred solution of Boc-L-Nle-ol (0.50 g, 1.9 mmol) in dry tetrahydrofuran (15 mL), cooled at 0° C. under nitrogen, NaH (0.05 g, 2.1 mmol) was added. The reaction mixture was stirred for 45 min at 0° C., followed by addition of 18-crown-6 (0.25 g, 0.9 mmol) and subsequently a solution of ethyl bromoacetate (0.47 g, 2.8 mmol) in dry tetrahydrofuran (4 mL) was added dropwise at 0° C. The reaction mixture was stirred for 1 h at 0° C. and overnight at room temperature. The organic solvent was evaporated under reduced pressure and the residue was purified by column-chromatography using chloroform as eluent. Yield 55%; Oil; [a]D=−13.9 (c 1CHCl3); 1H NMR (200 MHz, CDCl3) δ 4.85-4.78 (m, 1H), 4.17 (q, J=7.4 Hz, 2H), 4.03 (s, 2H), 3.72-3.58 (m, 1H), 3.56-3.41 (m, 2H), 1.62-1.21 (m, 18H), 0.85 (t, J=6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 170.3, 155.6, 78.9, 73.3, 68.4, 60.7, 50.3, 31.5, 28.3, 28.1, 22.5, 14.1, 13.9. Anal. Calcd for C15H29NO5: C, 59.38; H, 9.63; N, 4.62. Found: C, 59.16; H, 9.82; N, 4.51.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28](O)[CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CCOCC>[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:30][CH2:29][C@H:28]([O:1][C:2]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=2[C:4]([OH:6])=[O:5])[CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COCCOc1ccc(C(=O)OC)c(O)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Solvent: CCOCC
Product: COCCOc1ccc(C(=O)O)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1

Procedure:
Using a procedure similar to that of Example 29-A, methyl 2-hydroxy-4-(2-methoxyethoxy)benzoate (6.0 g, 26.52 mmol) is alkylated with trans-4-tert-butoxycarbonylamino-cyclohexanol (5.38 g, 26.52 mmol) to afford the ether (2.70 g), which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:8](=[N:12][O:13][CH3:14])[C:9]([NH2:11])=O)=[C:4]([F:23])[CH:3]=1.ClC(Cl)(Cl)C(Cl)=O>C(N(CC)CC)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:8](=[N:12][O:13][CH3:14])[C:9]#[N:11])=[C:4]([F:23])[CH:3]=1
Reactant: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(N)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(C#N)=NOC

Procedure:
The title compound is prepared by reaction of 3-(4-bromo-2-fluorobenzyl)-2-methoxyimino-4-oxooctanamide (from Step H) with trichloroacetyl chloride in the presence of triethylamine according to the procedure of Example 4, Step F. Alternatively, the following procedure is used. To 1 mmol of the amide from Step H is added about 12 mL of polyphosphate ester (PPE) [M. Cava, M. Lakshmikantham, and M. Mitchell, J. Org. Chem., 34, 2665 (1969)] solution, consisting of approximately a 2:1 ratio of PPE and CDCl3 (used as a surrogate for alcohol-free chloroform). The mixture is stirred at reflux under N2 for about 3 hours, and then the solvent is removed by concentration in vacuo. The residue is cooled in an ice bath and treated with an excess of saturated aqueous Na2CO3. The mixture is stirred for 1 hour and then extracted with ethyl acetate. The organic phase is washed further with H2O, then dried over Na2SO4, filtered, and concentrated. The residue is purified by column chromatography on silica gel (elution with hexane-EtOAc) to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22].O>O1CCCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][Br:16]
Reactant: NCc1ccccn1
Reactant: O=C(Cl)CCCCBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCBr)NCc1ccccn1
Reaction time: 12 h
Yield: 92.6 %

Procedure:
Part A. A solution of 2-(aminomethyl)pyridine (4.07 g, 37.6 mmol) and triethylamine (7.50 mL, 53.8 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C., then treated with a solution of 5-bromovaleryl chloride (5.00 mL, 37.6 mmol) in tetrahydrofuran (20 mL) dropwise. After stirring for 12 hours, the mixture was poured into water (150 mL) and extracted with methylene chloride (2×150 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the oily product, N-(2-pyridylmethyl)-5-bromopentanamide (9.44 g, 34.8 mmol, 93%).
Reaction SMILES: CO[CH2:3][C:4]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[C:7]([C@H:8]3[CH2:18][C@H:9]3[CH2:10][O:11]2)=[CH:6][CH:5]=1.C([Cl:22])(=O)C>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[Cl:22][CH2:3][C:4]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[C:7]([C@H:8]3[CH2:18][C@H:9]3[CH2:10][O:11]2)=[CH:6][CH:5]=1
Reactant: COCc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: COC(=O)c1c(CCl)ccc2c1OC[C@@H]1C[C@H]21

Procedure:
Zinc chloride (0.014 g) was added to a solution of methyl cis-(1aRS,7bSR)-5-methoxymethyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 7, 0.53 g) and acetyl chloride (0.77 mL) in anhydrous diethyl ether (50 mL) and the resultant mixture was stirred for 1.5 hours. The mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl cis-(1aRS,7bSR)-5-chloromethyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.486 g) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:43][C:44]([F:56])([F:55])[C:45]1[CH:54]=[C:53]2[C:48]([CH2:49][CH2:50][NH:51][CH2:52]2)=[CH:47][CH:46]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:16])[N:51]3[CH2:50][CH2:49][C:48]4[C:53](=[CH:54][C:45]([C:44]([F:43])([F:56])[F:55])=[CH:46][CH:47]=4)[CH2:52]3)[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.53-7.33 (m, 2H), 7.31-7.18 (m, 3H), 7.02 (td, J=3.4, 8.7, 2H), 4.74 (d, J=23.8, 2H), 4.31 (t, J=18.2, 1H), 4.20-4.02 (m, 1H), 3.86 (t, J=6.0, 1H), 3.78-3.69 (m, 2H), 3.66-3.53 (m, 2H), 3.04-2.87 (m, 2H), 2.66-2.49 (m, 1H), 2.27-2.09 (m, 1H); MS (DCI) m/z 421.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)C.Br>C(O)(=O)C.O.ClCCl>[NH2:11][C:9]1[S:10][C:6]2[CH:5]=[C:4]([OH:3])[CH:13]=[CH:12][C:7]=2[N:8]=1
Reactant: CCOc1ccc2nc(N)sc2c1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(O)cc2s1
Yield: 88.5 %

Procedure:
To a solution of 7 g of 6-ethoxy-1,3-benzothiazol-2-amine (commercial) in 65 cm3 of glacial acetic acid are added 130 cm3 of a 48% solution of hydrobromic acid in water. The solution is refluxed for about 20 hours. After concentrating to dryness under reduced pressure (13 kPa), the residue is taken up in 50 cm3 of water and the pH of the solution is brought to about 8 by addition of solid sodium hydrogen carbonate. The mixture is extracted with four times 250 cm3 of ethyl acetate and the combined organic phases are washed with three times 20 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The solid obtained is taken up in 20 cm3 of dichloromethane, filtered off by suction, washed with three times 10 cm3 of dichloromethane and then three times 20 cm3 of diethyl ether, and dried under reduced pressure (13 kPa) over phosphorus pentoxide. 5.3 g of 2-amino-1,3-benzothiazol-6-ol are thus obtained in the form of a pink powder, the characteristics of which are as follows: