Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+].O>O1CCOCC1>[N:30]([CH2:12][CH2:13][C@@H:14]1[CH2:16][C@@H:15]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (65 mg, 0.15 mmol) from step 1 of this example was dissolved in dioxane (1.2mL). Sodium azide (22.3 mg, 0.34 mmol) was added, then water (0.3 mL). The reaction was heated to 100° C. to reflux for 2 hours. The reaction was cooled to room temperature, water (10 mL) was added and extracted with EtOAc (10 mL×2). The combined organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 12 gram RediSep Rf™ silica gel cartridge eluting with 5% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]>>[F:21][C:4]1[CH:3]=[C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:31]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Methylsulfonyl benzene boronic acid. MS (M+H) 431.1
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.Cl>[OH:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:1]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(O)cc2OC1C(F)(F)F
Temperature: 60 °C
Yield: 31.6 %

Procedure:
A mixture of 2,4-dihydroxy benzaldehyde (20.0 g, 0.145 mole) and ethyl 4,4,4-trifluorocrotonate (36.58 g, 0.217 mole) was dissolved in anhydrous DMF (40 mL). The solution was warmed to 60° C., treated with anhydrous K2CO3 (40.0 g, 0.290 mole), and maintained at 80° C. for 48 h. The reaction was cooled to room temperature, diluted with 3N HCl, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford an oil. The oil was passed through the silica plug and the plug was washed with 20% EtOAc in hexane to give yellow solid (13.22 g, 31.6%): LCMS m/z 311.05 (M+Na). 1H NMR (CDCl3/400 MHz) 7.67 (s, 1H), 7.09 (d, 1H, J=8.8 Hz), 6.46 (m, 2H), 5.67 (q, 1H, J=6 Hz), 4.29 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31](N2C=CN=C2)=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]>C1COCC1>[C:22]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[N:4]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1cccc(NC(=O)n2ccnc2)c1
Reactant: CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2cccc(C#N)c2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
3-Amino-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2,4-dioxo-1H-1,5-benzodiazepine (360 mg) was suspended in dry THF (10 ml) under nitrogen. N-(3-cyanophenyl)-1H-imidazole-1-carboxamide (326 mg) was added, and the mixture stirred at room temperature for 2 h. The mixture was filtered to give the title compound (510 mg) as a white solid m.p.>250°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([N:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][C:20]2=[O:26])[CH2:18][CH2:17]1.CCN(CC)CC>ClCCl>[CH:16]1([N:19]2[CH:24]=[CH:23][C:22]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:21][C:20]2=[O:26])[CH2:18][CH2:17]1
Reactant: O=c1cc(O)ccn1C1CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1cc(OS(=O)(=O)C(F)(F)F)ccn1C1CC1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.12 mL) was added to a flask charged with a stir bar, 1-cyclopropyl-4-hydroxy-1H-pyridin-2-one (0.10 g), NEt3 (0.24 mL), and dichloromethane (8 mL) and chilled in an ice/EtOH bath. The resulting mixture was stirred with cooling for 2 h and at ambient temperature for another 2 h. Then, the solution was diluted with dichloromethane and washed in succession with water, aqueous NaHCO3 solution, and water. The organic solution was dried (MgSO4), the solvent was removed, and the residue was purified by chromatography on silica gel (dichloromethane/methanol 99:1->90:10) to afford the title compound as a resin-like solid. Yield: 0.07 g (36% of theory). Mass spectrum (ESI+): m/z=284 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25](=[NH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:22][N:36]=[C:25]([C:26]5[CH:27]=[C:28]([S:32]([NH2:33])(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(Cl)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) (157 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as an off-white solid (113 mg, 46%). MS (EI) 492.1 [(M)+]; mp 285° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH:8]([CH2:10][CH3:11])[CH3:9])=[CH:4][CH:3]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]([CH2:10][CH3:11])[CH3:9])[C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:22])=[CH:12][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCC(C)NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: CCC(C)N(Cc1ccc(Cl)cc1)C(=O)Nc1ccccc1
Yield: 92.6 %

Procedure:
30 g (0.15 mole) of N-(4-chlorobenzyl)N-sec.-butylamine were dissolved in 500 ml of ether. To the resulting solution, a solution of 18 g (0.15 mole) of phenyl isocyanate in 50 ml of ether was added dropwise, under cooling and stirring. After the dropwise addition, the temperature of the solution was gradually raised, and the solution was then stirred at room temperature for about 10 hours. The crystals which had been formed were separated by filtration. After recrystallization with a solvent mixture of hexane and ethyl alcohol, 44 g of N-(4-chlorobenzyl)-N-sec.-butyl-N'-phenylurea were obtained. Yield: 93%. Melting point: 80°-81.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](OC(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2)#[N:2].Cl>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[CH:33]2)#[N:2]
Reactant: CC(C)(C)OC(=O)ON1CCC(COc2cc3nccc(Oc4ccc5[nH]ccc5c4)c3cc2C#N)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OCC1CCNCC1
Reaction time: 17 h
Yield: 7.5 %

Procedure:
6-Cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline (0.25 g, 0.5015 mmol) was dissolved in ethanol (2 ml) and tetrahydrofuran (2 ml), and then concentrated hydrochloric acid (0.2 ml) was added at room temperature and the mixture was stirred for 17 hours. The solvent was distilled off under reduced pressure, saturated bicarbonate water was added, and then extraction was performed with a tetrahydrofuran and ethyl acetate mixed solvent, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto NH silica gel and purified by column chromatography (ethyl acetate-methanol system) with NH silica gel, and the obtained crystals were suspended in ethanol and diluted with diethyl ether and hexane. The crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (15 mg, 0.0376 mmol, 7.51%).
Reaction SMILES: I[CH2:2][C:3](=[O:5])[CH3:4].[P:6]([O:13]CC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>>[CH2:2]([P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[C:3]([CH3:4])=[O:5]
Reactant: CCOP(OCC)OCC
Reactant: CC(=O)CI
Product: CCOP(=O)(CC(C)=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.3 %

Procedure:
Iodoacetone (56.5 g., 0.31 mole) was added dropwise over a 20 minute period to 41.4 g (0.31 mole) of triethyl phosphite at 0° C. The mixture was allowed to warm to room temperature and held there for 90 minutes. The crude product was distilled in vacuo and the fraction boiling at 76°-86° C. (0.3-0.35 mm) was collected, giving 12.2 g of diethyl acetonylphosphonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH2:10][CH:9]2[O:22]C(OCC(Cl)(Cl)Cl)=O)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[OH:22])=[CH:4][CH:3]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)OC1CN(C(=O)OCC(Cl)(Cl)Cl)CCC1c1ccc(Br)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: OC1CNCCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.5 %

Procedure:
A mixture of 1.3 g (2.1 mmol) of 2,2,2-trichloroethyl (3RS,4RS)-4-(4-bromo-phenyl)-3-(2,2,2-trichloro-ethoxy-carbonyloxy)-piperidine-1-carboxylate 1.54 g of activated zinc in 20 ml of glacial acetic acid was stirred at room temperature for 5 hours. For the working-up, the zinc was filtered off, the residue was rinsed with glacial acetic acid and the solution was subsequently evaporated to dryness under reduced pressure. The residue was partitioned between 20 ml of saturated sodium carbonate solution and 30 ml of ethyl acetate, thereafter the separated aqueous phase was extracted twice with 30 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. Crystallization of the residue using a 1:2 mixture of ethyl acetate and hexane yielded 250 mg (46% of theory) of (3RS,4RS)-4-(4-bromo-phenyl)-piperidin-3-ol as a colourless solid; MS: 255, 257 (M)+. The mother liquor was purified by chromatography on silica gel using a 4:1 mixture of methylene chloride and methanol as the eluent. A further 101 mg (18% of theory) were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CO.[Zn]>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1

Procedure:
2-(4-Benzyloxyphenoxy)-5-nitropyridine (7.84 g, 24.32 mmol) and zinc (15.16 g, 231.8 mmol) were suspended in 300 ml of methanol. Under argon 5.2 ml of acetic acid were slowly added dropwise at room temperature. After 1 h the mixture was filtered and the filtrate was concentrated. The crude product obtained was further reacted without purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.C(OCC)(=O)C>C1COCC1>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[S:9][C:8]2=[C:4]([S:3][C:2]([F:1])([F:12])[F:13])[N:5]=[CH:6][N:7]2[CH:11]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)(F)Sc1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC(F)(F)F)c2s1
Temperature: -65 °C

Procedure:
7-Trifluoromethylthioimidazo[5,1-b]thiazole (590 mg) was dissolved in 10 ml of THF under an argon atmosphere, and the solution was cooled to −65° C. Tri-n-butylstannyl chloride (2.07 ml) and 7.2 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added dropwise in that order to the cooled solution. The temperature of the mixture was raised to −40° C. over a period of 30 min. Ethyl acetate (40 ml) was added to the reaction solution, and the mixture was washed with 40 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, and was then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to prepare 951 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: CC(C)(C)O
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 40 °C
Reaction time: 48 h

Procedure:
3-Chloro-4-methoxycarbonylbenzoic acid (0.24 g) was dissolved in DMF (2.5 mL) under N2 then CDI (0.36 g) was added and the resulting mixture was stirred at 40° C. for 2 h. t-BuOH (0.54 mL) and DBU (0.33 mL) were added and the resulting mixture was stirred at 40° C. for 2 days. The mixture was evaporated and the residue was taken up with AcOEt, washed with 1N HCl and sat NaHCO3, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: toluene) to give 2-chloro-4-(tert-butoxycarbonyl)benzoic acid methyl ester (216 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][CH:34]=3)[CH2:18][CH2:17]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(=O)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Nc3ccc(F)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
To a solution of the compound obtained in Example 208 (1000 mg, 2.2 mmol) and 4-fluoroaniline (269 mg, 2.4 mmol) in THF (3 mL) were added acetic acid (0.126 mL, 2.2 mmol) and sodium triacetoxyborohydride (699 mg, 3.3 mmol) under ice cooling, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate (100 mL). The mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate (100 mL×2). The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 20 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (695 mg, 1.3 mmol, Yield 58%) as a pale purple amorphous substance.
Reaction SMILES: [CH:1]([CH:4](Cl)[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2].[C-:16]#[N:17].[Na+].[OH-].[Na+]>O.C(N(CC)CC)C>[CH:1]([CH:4]([C:16]#[N:17])[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: COc1ccc(C(Cl)C(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)C(C)C)cc1OC

Procedure:
457.4 g (2 mol) of α-isopropyl-veratryl chloride, 108 g (2.2 mol) of sodium cyanide, 10 mol-% of phase transfer catalyst, 100 ml of water and 800 ml of triethylamine are stirred together for 5 hours at 60° C. After the addition of 60 ml of 30% sodium hydroxide solution and 300 ml of water, the organic phase is separated off. After removal of the triethylamine by distillation, the residue is distilled in a fine vacuum. The distillate obtained is recrystallised from methanol/water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][C:11]([NH2:13])=[S:12].BrBr>C(Cl)(Cl)Cl>[NH2:13][C:11]1[S:12][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:10]=1
Reactant: COc1ccc(Cl)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)c2sc(N)nc12
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-methoxy-5-chlorophenyl)-2-thiourea (1 mmole) in chloroform (10 mL) was cooled to 10° C. and treated with bromine (2.2 mmole) in chloroform (10 mL). The reaction was stirred at 10° C. for 20 min and at room temperature for 0.5 h. The resulting suspension was heated at reflux for 0.5 h. The precipitate was collected via filtration (washed with CH2Cl2) to give 2-amino-4-methoxy-7-chlorobenzothiazole which was subjected to Steps A, B, C and D of Example 27 to give 2-amino-4-phosphonomethoxy-6-bromo-7-chloro benzothiazole (28.1). mp>220° C.(dec.). Anal. calcd. for C8H7N2O4PSClBr: C: 25.72; H: 1.89; N: 7.50. Found: C: 25.66; H: 1.67; N: 7.23.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:1]([CH2:8][C:9]([O:11][CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=C(O)COc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(COc1ccccc1)OCCO

Procedure:
A 2-liter, 3-neck, round-bottom flask was equipped with a heating jacket, thermocouple and Dean-Stark apparatus for water removal. The flask was charged with 152 g (1.0 mole) phenoxyacetic acid, 62 g (1.0 mole) ethylene glycol, 22 g p-toluenesulfonic acid, 260 ml mixed xylenes and swept with nitrogen and sealed under a nitrogen balloon. The flask contents were heated to a pot temperature of 150° C. for 1/2 hour wherein 23 ml of water were collected and the reaction system cooled. Volatiles were removed at 110° C. in 4 mm of Hg vacuum to give a waxy white solid, IR shows formation of ester and disappearance of acid carbonyl, and mass spectrometry shows the molecular weight of 196.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([NH:5][OH:6])=[O:4].[CH2:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:15][CH3:16].C(N(C(C)C)C(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[OH:6][NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)NO
Reactant: CCCOc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(S(=O)(=O)N[C@H](Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 400 mg (˜0.33 mmol) resin from stage 1.1 are added successively dry dichloromethane (2 ml), 4-dimethylaminopyridine (4 mg, 0.033 mmol), 4-propoxy-benzenesulfonyl chloride (309.8 mg, 1.32 mmol) dissolved in dry dichloromethane (1 ml), and N-ethyldiisopropylamine (0.28 ml, 1.64 mmol). After shaking for 15 h at r.t. the suspension is filtered and the resin washed with dichloromethane (3×), alternating with DMA and H2O (2×), 0.2M aqueous citric acid, alternating with DMA and H2O (2×), alternating with 2-propanol and THF (3×), and with dichloromethane (4×). The resin is dried under reduced pressure to provide polymer-bound (R)—N-hydroxy-3-phenyl-2-(4-propoxy-benzenesulfonylamino)-propionamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CC([O-])(C)C.[Na+]>CCOCC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: BrCCOCCBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(F)c(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture 2-(3,4-difluorophenyl)acetonitrile (25.00 g, 163 mmol) and 2-bromoethyl ether (22.8 mL, 163 mmol) in ether was added dropwise through an addition funnel to a mixture of sodium 2-methylpropan-2-olate (39.2 g, 408 mmol) in DMF (163 mL) at 0° C. The reaction was then allowed to warm to ambient temperature and stirred for 3 hours. The reaction mixture was quenched with 12N HCl, diluted with 400 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 100 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound which was used without further purification. MS (m/z)=224 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Br:21].[Cl:22]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>O1CCCC1>[Cl:22][C:19]1[C:14]([F:13])=[C:15]([Br:21])[CH:16]=[CH:17][C:18]=1[F:20]
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1ccc(Br)c(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 19 ml (0.135 mole) of diisopropylamine in 125 ml of tetrahydrofuran (THF) cooled at −20° C. is added 80 ml of n-butyllithium (1.6 M in hexane). The temperature is raised to 0° C. for 5 minutes and lowered to −78° C. Then 25 g (0.129 mole) of 2,4-difluoro-bromobenzene is then added and the reaction is stirred at −65° C. for 2 hours. Then, 25 ml (0.164 mole) of hexachloroacetone is added and the solution is warmed to room temperature. After evaporation of the solvent, the residue is distilled under vacuum to give the desired product.