Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([CH2:35][CH2:36][C:37](=[O:40])[NH:38][OH:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:43][O:44][C:45]([CH3:61])([CH3:60])[C:46]([NH:48][NH:49][C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=1)=[O:47]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][C:45]([C:46](=[O:47])[NH:48][NH:49][C:50](=[O:59])[C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=2)([CH3:60])[CH3:61])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([CH2:35][CH2:36][C:37](=[O:40])[NH:38][OH:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Cc1nc2nc(CCC(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(CCC(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.5 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-[2-(hydroxycarbamoyl)ethyl]-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (41 mg) (0.66 mmol) and 29 mg of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 1 ml of absolute dimethylacetamide. After stirring at room temperature for 20 hours the solvent is removed at room temperature in a high vacuum. The residue is crystallized from ethanol/diethyl ether. The product is filtered off, washed with diethyl ether, water and again with diethyl ether. After drying in a high vacuum at room temperature there are obtained 45 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[5-[2-(hydroxycarbamoyl)ethyl]-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.F[C:34](F)(F)[C:35](O)=[O:36].ClCCO.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:34][CH2:35][OH:36])[CH2:12][CH2:13]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OCCCl
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(CCO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of (S)-N-[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.400 g, 0.881 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (7 mL) at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resultant amber syrup combined with 2-chloroethanol (354 μL, 5.27 mmol), potassium carbonate (0.730 g, 5.27 mmol), and acetonitrile (20 mL) and the mixture heated to reflux for 24 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude product was chromatographed over silica gel (10 g), eluting with 1%, 3%, and then 6% methanol/chloroform, to afford, after concentration of appropriate fractions, 0.067 g (19%) of the title compound as an off-white solid with mp 172°-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:25])[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=3)[C:16](=O)[C:15]3[C:14]([C:27]([O:29]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:33][NH:34][C:27](=[O:29])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:25])[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nc(C)c(C)n1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1nc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)n(C)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-4-oxo-3-(1,4,5-trimethyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg) in 85% hydrazine monohydrate (85%, 3 mL) and methanol (5 mL) was stirred at room temperature for 2 days. The result suspension was filtered and washed the water (20 mL) and methanol (5 ml) to obtain a white solid. The solid was dried in vacuum at 50° C. to afford the title compound (90 mg, yield 65%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.91-1.96 (d, J=18 Hz, 6H), 3.25 (s, 3H), 4.59-4.62 (d, J=10.8 Hz, 1H), 4.92-4.95 (d, J=10.8 Hz, 1H), 7.09-7.15 (m, 3H), 7.22 (s, 1H), 7.36-7.38 (d, J=7.6 Hz, 1H), 7.43-7.46 (m, 2H), 7.54-7.58 (t, J=8 Hz, 1H), 12.13 (s, 1H); LC-MS (ESI) m/z: 390 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][CH2:9]C2SC=CC=2)=[N:6][CH:7]=1.[CH3:32][CH:33]([C:35]1[O:39]C(N)=[N:37][CH:36]=1)[CH3:34]>>[Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][P:25]([CH3:29])(=[O:28])[CH2:26][CH2:27]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][C:9]2[O:39][C:35]([CH:33]([CH3:34])[CH3:32])=[CH:36][N:37]=2)=[N:6][CH:7]=1
Reactant: CC(C)c1cnc(N)o1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(NCc2cccs2)ncc1Cl
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(Nc2ncc(C(C)C)o2)ncc1Cl

Procedure:
The compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (as described in Example 47) with 5-(propan-2-yl)-1,3-oxazol-2-amine.
Reaction SMILES: [C:1]1(=O)[O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:11]([O:18][C:19](=[O:25])[C@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:55]([O:57][C:58](=[O:64])[C@H:59]1[CH2:63][CH2:62][CH2:61][NH:60]1)[CH3:56]>ClCCl>[CH2:11]([O:18][C:19]([C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:60]1[CH2:61][CH2:62][CH2:63][C@@H:59]1[C:58]([O:57][CH2:55][CH3:56])=[O:64])=[O:7])=[O:25])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: CCOC(=O)[C@H]1CCCN1
Reactant: O=C1CCCCC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
A mixture of 403 mg (3.15 mmol) adipic acid anhydride, 604 mg (2.5 mmol) D-proline-benzyl-ester hydrochloride and 274 ml (2.5 mmol) N-methyl-morpholin in 10 ml dichloromethane was stirred at room temperature for 1 hour. Then 0.5 g polymer bound primary amine (2 meq/g) were added and stirring was continued for 1 hour. After filtration 823 ml (7.5 mmol) N-methyl-morpholin, 338 mg (2.5 mmol) 1-hydroxybenzotriazole, 479 mg (2.5 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 450 mg (2.5 mmol) D-proline-ethyl-ester were added and the mixture was stirred for another 48 hours. Removal of the solvent and chromatography on silicagel with ethylacetate gave 135 mg (12%) (R)-1-[6-[(R)-2-ethoxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid benzyl ester as a light yellow oil, MS m/e (%): 459 (M+H+, 100).
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29]>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[C@@H:27]1[N+:28]([O-:30])=[O:29])=[O:9])[CH3:12]
Reactant: COc1ccccc1/C=C/[N+](=O)[O-]
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCC)[C@@H](c2ccccc2OC)[C@@H]1[N+](=O)[O-]
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq) and 1-methoxy-2-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethyl ether (0.4 mL) was added catalyst VI (Q-NH2) (0.06 mmol, 0.2 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 24 hours, then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Et2O:Hexane=1:10 to 1:3) in 81% yield.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][C:20]=1[O:28][CH3:29]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]([F:30])[F:15])=[C:20]([O:28][CH3:29])[CH:21]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COc1cc(C(C)N)ccc1OCC(F)F
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: COc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (154 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanamine hydrochloride (152 mg, 0.57 mmol, Amine-31, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.[O:22]1C[CH2:25][CH2:24][CH2:23]1.C([O-])(=O)C=C.[Cl-]>C1(C)C=CC=CC=1.O>[C:23]([O:10][CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])=[CH:5][CH:6]=1)(=[O:22])[CH:24]=[CH2:25]
Reactant: C1CCOC1
Reactant: CCN(CC)c1ccc(CCO)cc1
Agent: C=CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCc1ccc(N(CC)CC)cc1
Temperature: 0 °C

Procedure:
In a three-aperture flask, 5.43 g (28.1 mmol) of p-diethylaminophenethyl alcohol, 6.26 g (61.8 mmol) of triethylamine, and 30 mL of dehydrated tetrahydrofuran were poured, and the mixture was stirred under an argon atmosphere and an ice-cooling condition. Then, 5.09 g (56.2 mmol) of chloride acrylate was delivered by drops into the reaction solution for 30 minutes. Upon completion of the dripping, the reaction solution was further stirred for 5 hours. The reaction solution was poured to 100 mL of water and then an extract was obtained therefrom by using toluene, followed by washing with water three times. The toluene solution was dried with anhydrous magnesium sulfate, and then the solvent was distilled away to purify the toluene solution by silica gel chromatography using a mixture solvent of hexane/ethyl acetate (9/1) as an eluent to thereby synthesize 3.17 g (yield: 46% by mass) of p-diethylaminophenethyl acrylate of the exemplified compound No. 21 represented by the following structural formula.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][P:7](O)(O)=O)[C:2]([OH:4])=[O:3].[NH3:11]>>[CH2:1]([NH:5][CH2:6][PH2:7])[C:2]([O-:4])=[O:3].[NH4+:11].[NH3:5]
Reactant: O=C(O)CNCP(=O)(O)O
Agent: N
Product: O=C([O-])CNCP
Product: [NH4+]

Procedure:
The present invention is further directed to a continuous process for preparing a granular herbicidal composition, comprising continuously feeding (i) particulate glyphosate acid, (ii) ammonia, (iii) adjuvant, and (iii) water to form a reaction mass in which ammonium glyphosate is formed, wherein the amount of water fed is from about 10% to about 25% by weight of all materials being fed to the reactor. The reaction of glyphosate acid and ammonia generates heat, causing the evaporation of water such that the water content of the reaction mass is reduced to from about 2% to about 10% to form an ammonium glyphosate paste. The reaction mass is continuously conveyed to the product discharge region of the reactor and as part of the process, the adjuvant (i) increases the rate at which the glyphosate acid and ammonia react to form ammonium glyphosate and/or (ii) reduces the flow resistance of the reaction mass as it is being conveyed to the product discharge region of the reactor.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]3[NH:18][C:17](=[O:19])[C:16]3([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:26]([O:33][C:34]([C:36]1[CH:45]=[CH:44][C:39]([CH2:40][N:41]=[C:42]=[O:43])=[CH:38][CH:37]=1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]3[N:18]([C:42]([NH:41][CH2:40][C:39]4[CH:44]=[CH:45][C:36]([C:34]([O:33][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:35])=[CH:37][CH:38]=4)=[O:43])[C:17](=[O:19])[C:16]3([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CCC1(CC)C(=O)NC1Oc1ccc(C(=O)N2CCN(C)CC2)cc1
Reactant: O=C=NCc1ccc(C(=O)OCc2ccccc2)cc1
Product: CCC1(CC)C(=O)N(C(=O)NCc2ccc(C(=O)OCc3ccccc3)cc2)C1Oc1ccc(C(=O)N2CCN(C)CC2)cc1

Procedure:
According to the method of Shrenik et al (J. Med. Chem., 35, 3745-3754 (1992)), 4-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-2-azetidinone (160 mg, 0.463 mmol) and 4-(benzyloxycarbonyl)benzylisocyanate (261 mg, 0.98 mmol) gave, following purification by flash column chromatography (MeOH/EtOAc, 1:4), the title compound (171 mg, 60%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[S-:10][C:11]#[N:12].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][S:10][C:11]#[N:12]
Reactant: ClCc1cccc(Cl)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: N#CSCc1cccc(Cl)c1

Procedure:
The starting material is prepared as follows: 250 g of m-chlorobenzyl chloride, 16.6 g of potassium thiocyanate and 150 ml of 95% aqueous ethanol is refluxed for 3 hours and evaporated. The residue is taken up in methylene chloride and water, the organic solution separated, washed with water, dried and evaporated to yield the m-chlorobenzyl thiocyanate.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[O:7]1[C:9]([CH3:11])([CH3:10])[CH2:8]1.[NH:12]1[CH2:15][CH:14]([C:16]2[CH:17]=[CH:18][C:19]3[O:28][CH2:27][CH2:26][C:25]4[S:24][C:23]([C:29]5[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=5)=[N:22][C:21]=4[C:20]=3[CH:37]=2)[CH2:13]1>C1COCC1>[CH:34]([N:30]1[C:29]([C:23]2[S:24][C:25]3[CH2:26][CH2:27][O:28][C:19]4[CH:18]=[CH:17][C:16]([CH:14]5[CH2:13][N:12]([CH2:8][C:9]([CH3:11])([OH:7])[CH3:10])[CH2:15]5)=[CH:37][C:20]=4[C:21]=3[N:22]=2)=[N:33][CH:32]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC1(C)CO1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CC(C)(C)O)C3)cc1-2
Reaction time: 0.21 h
Yield: 35.7 %

Procedure:
Lithium perchlorate (52 mg, 0.49 mmol) was added to THF (5 mL) followed by 1,2-epoxy-2-methylpropane (0.43 mL, 4.9 mmol) and the mixture was stirred for 10-15 minutes giving a clear solution. 9-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol) was added and the reaction mixture was stirred for 72 hours then concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-10% MeOH in EtOAc) and the resulting solid extracted several times with ether. The ether extracts were concentrated in vacuo to give 377 (77 mg, 97%). LCMS: RT=7.45 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.28 (1H, d, J=2.34 Hz), 7.90 (1H, s), 7.16 (1H, dd, J=8.29, 2.35 Hz), 7.02 (1H, d, J=8.27 Hz), 5.93-5.83 (1H, m), 4.40-4.34 (2H, m), 4.04-3.95 (2H, m), 3.89-3.79 (1H, m), 3.46-3.36 (4H, m), 2.55 (2H, s), 1.63 (6H, d, J=6.64 Hz), 1.15 (6H, s). 1 Exchangeable proton not seen
Reaction SMILES: C([N:8]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH2:9][CH:10]([OH:26])[CH2:11][O:12][C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH:16]1[C:17]2[NH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[C:13]([O:12][CH2:11][CH:10]([OH:26])[CH2:9][NH:8][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH:14][CH:15]=1
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 50 °C
Reaction time: 7 h

Procedure:
10 g of 1-{Benzyl-[2-(2-methoxy-phenoxy)-ethyl]-amino}-3-(9H-carbazol-4-yloxy)-propan-2-ol (20 mmol) were dissolved in 80 ml methanol. 1 g of Pd-C (10%) were added and the suspension was warmed to 50° C. The mixture was hydrogenated at normal pressure for about 7 hours. The Pd-catalyst was filtered under suction and washed with 25 ml of hot methanol. 80 ml of methanol were distilled off and the residue was cooled to 0° C. and hold at this temperature for 6 h. The product was filtered and washed twice with 3 ml cold methanol. The substance was dried at 60° C. for 12 h.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl.Cl>[CH3:12][O:11][C:8]1[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2CCOC2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1CCOC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [6-methoxy-2′-(2-oxo-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.117 g, 0.28 mmol) in THF (1.2 mL) and MeOH (0.9 mL) was added 1N aqueous NaOH (0.61 mL), and the reaction was stirred at room temperature for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was diluted with CH2Cl2 and aqueous HCl. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound. M+H is 410.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][C:24]([NH2:26])=[O:25])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.[CH:27]([NH2:30])([CH3:29])[CH3:28]>O1CCOCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][C:24]([NH2:26])=[O:25])[N:10]=2)[CH:5]=[N:6][C:7]=1[NH:30][CH:27]([CH3:29])[CH3:28]
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4cnc(Cl)c(Cl)c4)n3)cccc21
Reactant: CC(C)N
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(C)Nc1ncc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1Cl
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 2-{4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) in dioxane (2 ml) and NMP (2 ml) was added isopropylamine (220 μl), followed by stirring at 150° C. for 1 hour in a microwave reaction vessel. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:EtOAc=40:60 to 0:100), and the obtained residue was suspended in diisopropyl ether under heating, and collected by filtration to obtain 2-(4-{5-[5-chloro-6-(isopropylamino)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (62 mg) as white powders.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8](C(O)=O)[CH:7]=[CH:6][C:5]=12.C([N:15](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[NH2:15][C:8]1[CH:7]=[CH:6][C:5]2=[N:1][O:2][N:3]=[C:4]2[CH:9]=1
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ccc2nonc2c1
Temperature: 105 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a solution of 2,1,3-benzoxadiazole-5-carboxylic acid (102 mg, 0.621 mmol) in THF (3 mL) was added triethylamine (103 mL, 0.739 mmol) followed by DPPA (160 μL, 0.739 mmol) at room temperature. The mixture was stirred for 4 h, diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4, concentrated and purified by flash chromatography on silica gel with 0 to 50% EtOAc in CH2Cl2. The resulting material was dissolved in AcOH (2 mL) and water (0.7 mL) was added dropwise yielding a slightly cloudy solution which was heated at 105° C. for 30 min. The mixture was cooled, made basic with sat. Na2CO3 solution and extracted several times with THF. The combined organic layers were dried over MgSO4, concentrated and purified by flash chromatography on silica gel eluting with 0 to 15% MeOH in CH2Cl2 to give 34 mg (41%) of compound 480A as a yellow solid. HPLC: 100% at 1.27 min (retention time) (YMC S5 ODS column, 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 min containing 0.2% H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 136.0 [M+H]+.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Si:8]([O:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:27]1[C:38](OC)=[O:39])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>CCCCCC>[Si:8]([O:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:27]1[CH2:38][OH:39])([C:21]([CH3:23])([CH3:24])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1CO
Yield: 207.7 %

Procedure:
2.0 M of a solution of (trimethylsilyl)diazomethane in hexane (40 mL) was added dropwise to 1-tert-butyl 2-methyl (2S,3S)-3-{[tert-butyl(diphenyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (11.6 g) and methanol (50 mL) with stirring. The reaction solution was concentrated and the residue was added dimethylformamide (100 mL), tert-butyldiphenylchlorosilane (13.7 mL) and imidazole (6.37 g) and stirred at room temperature for overnight. The reaction solution was added water and extracted with a mixture solution of hexane/ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was added tetrahydrofuran (100 mL), methanol (3 mL) and lithium borohydride (2.51 g) at 0° C. and stirred at room temperature for 1 hour. The reaction solution was added water and aqueous 5% potassium sulfate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→75:25) to obtain the title compound (22.7 g) having the following physical properties.