Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(=O)([O-])O.[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:32])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCC(=S)N2
Temperature: 105 °C
Reaction time: 1.17 h
Yield: 183.2 %

Procedure:
A solution of 20.0 g of 5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepin-2(1H)-one (G. M. Clarke, J. B. Lee, F. J. Swinbourne & B. Williamson, J. Chem. Res. Synop. 1980, 400) in 100 ml of hexamethylphosphoric acid triamide was treated with 14 g of Lawesson reagent and the mixture was stirred at 105° C. for 70 min. The reaction mixture was poured into 800 ml of saturated aqueous sodium hydrogen carbonate solution and 800 ml of water. After stirring at room temperature for 15 min. the precipitate was filtered off, washed with water and dried. There were obtained 20 g of crude 5-(2-fluorophenyl)-7-nitro-3H-1,4-benzodiazepine-2(1H)-thione, which was used in this form for the next step.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@H:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@@H:17]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[O:15])C1C=CC=CC=1.[OH:30]O.O.[OH-].[Li+]>C1COCC1.O>[Si:23]([O:22][C@@H:17]1[C@@H:16]([C:14]([OH:15])=[O:30])[CH2:21][C@H:20]2[C@@H:18]1[CH2:19]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: OO
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of (R)-4-benzyl-3-((1S,2S,3S,5S)-2-(tert-butyldimethylsilyloxy)bicyclo[3.1.0]hexane-3-carbonyl)oxazolidin-2-one (40 g, 96.4 mmol) in THF (200 mL) and water (50 mL) was added 30% aqueous hydrogen peroxide (88 mL, 771 mmol) dropwise at 0° C., followed by the addition of a solution of lithium hydroxide monohydrate (16 g, 386 mmol) in water (100 mL). After stirring for 1 hour at 0° C., the reaction mixture was stirred at room temperature overnight. The excess hydrogen peroxide was completely consumed by the addition of saturated aqueous sodium bisulfate. The mixture was then adjusted to pH=14 with 1 N NaOH and washed with ether (400 mL). The aqueous layer was then acidified to pH=3 with 1 M aqueous potassium hydrogen sulfate, and extracted with ethyl acetate (3×400 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (22 g, 88%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:13])=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[Cl:14]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1.[K+].[Br-]>C(#N)C.C(OCC)(=O)C>[Cl:14][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH2:13])=[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])[CH:6]=1
Reactant: CCc1cccc(S(N)(=O)=O)c1N
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C1CCC(=O)N1
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1cc(Cl)cc(S(N)(=O)=O)c1N

Procedure:
To a solution of 3-ethyl-2-aminobenzenesulfonamide (0.5043 g, 2.52 mmol) in 10 mL acetonitrile was added N-chlorosuccinimide (0.3163 g, 2.37 mmol). The mixture was stirred at reflux for 1 2.5 h, cooled, filtered, and concentrated in vacuo. Reaction was incomplete by 1H NMR; the purple solids were redissolved in acetonitrile and additional NCS (0.1019 g, 0.76 mmol) was added. The mixture was refluxed for 1 5 minutes and worked up as before. Column chromatography on the mixture of succinimide and D (40% ethyl acetate:hexanes) gave pure D (0.5224 g, 94%), m.p. 134-135° C. 1H NMR (300 MHz, DMSO): δ7.45 (3H, s), 7.19 (1H, d, J=2.1 Hz), 5.76 (2H, s), 2.53 (2H, q, J=7.3 Hz), 1.14 (3H, i, J=7.3 HZ). 13C NMR (300 MHz, DMSO): δ141.9, 131.8, 131.2, 125.4, 124.8, 118.1, 23.4, 12.7. FT-IR (KBr): 3457.8, 3427.9, 3358.4, 3268.9, 3080.1, 2970.8, 2364.5, 2334.7, 1630.6. 1556.1, 1541.2. 1451.7. 1312.6. 1188.3, 1148.6, 905.1, 875.3, 762.2, 611.3 cm-1. HRMS: M+ calculated=234.0230, found=234.0227.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=O)[CH3:2].[C:14](Br)(Br)([Br:16])[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:15][C:14]([Br:16])=[CH:5][C:4]1[C:3]([CH2:1][CH3:2])=[C:10]([F:11])[CH:9]=[CH:8][C:7]=1[CH2:12][CH3:13]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1ccc(F)c(CC)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(F)c(CC)c1C=C(Br)Br

Procedure:
2-(2,2-Dibromo-vinyl)-1,3-diethyl-4-fluoro-benzene was prepared from 2,6-diethyl-3-fluoro-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.15 (3H, t, CH3), 1.18 (3H, t, CH3), 2.58 (4H, m, 2×CH2), 6.97 (1H, dd, ArH), 7.04 (1H, dd, ArH), 7.42 (1H, s, CH═CBr2).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH3:8][S:9]([CH2:12][CH2:13][NH2:14])(=[O:11])=[O:10]>C(O)C>[CH3:8][S:9]([CH2:12][CH2:13][NH:14][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)CCN
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CS(=O)(=O)CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (865 mg) in ethanol (10 mL) was added 2-(methylsulfonyl)ethanamine (1 g), and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration to give the title compound (1.39 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH3:21][CH:20]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[CH3:22]
Reactant: CC(C)I
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1ccc2c(c1)C(=O)CCC2
Temperature: 80 °C

Procedure:
A suspension of 2.0 g of 7-hydroxy-3,4-dihydronaphthalen-1(2H)-one, 4.04 g of caesium carbonate and 3.15 ml of 2-iodopropane in 23 ml of acetonitrile is heated for 1 hour at 80° C. The reaction medium is brought back to ambient temperature and then evaporated to dryness. The residue is taken up with 100 ml of water and 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure, so as to obtain 2.24 g of 7-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in the form of an orangey-coloured oil.
Reaction SMILES: [AlH4-].[Li+].[CH2:3]([P:5]([CH2:12][CH:13]([CH3:16])[CH:14]=[O:15])(=[O:11])[O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:4].O>C(OCC)C>[CH2:3]([P:5]([CH2:12][CH:13]([CH3:16])[CH2:14][OH:15])(=[O:11])[O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:4]
Reactant: CCCCOP(=O)(CC)CC(C)C=O
Agent: [AlH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCOP(=O)(CC)CC(C)CO
Yield: 85 %

Procedure:
At room temperature, 2.3 g (0.06 mol) of lithium aluminohydride in 100 ml of absolute diethyl ether in a three-neck flask equipped with stirrer, dropping funnel and high-performance condenser are, while continuously stirring, admixed with a solution of 22.0 g (0.1 mol) of butyl ethyl(2-methyl-2-formylethyl)phosphinate in 100 ml of diethyl ether added dropwise at such a rate that there is a moderate boil of the diethyl ether. On completion of the dropwise addition the reaction solution is refluxed for 1 hour and subsequently admixed with 1.8 g (0.1 mol) of water. The insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo and the product is purified by chromatography to obtain 18.9 g (85% of theory) of butyl ethyl(2-methyl-3-hydroxypropyl)phosphinate as colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:6](OCC1N(CCCCNS(C)(=O)=O)C2C3C=CC=CC=3N=C(N)C=2N=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:33][C:34]1[C:43]2[N:44]=[C:45]([CH2:52][OH:53])[N:46]([CH2:47][C:48]([CH3:51])([OH:50])[CH3:49])[C:42]=2[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[N:35]=1.NC1C2N=C(CO)N(CCCCNS(C)(=O)=O)C=2C2C=CC=CC=2N=1>>[NH2:1][C@H:2]([C:6]([O:53][CH2:52][C:45]1[N:46]([CH2:47][C:48]([OH:50])([CH3:49])[CH3:51])[C:42]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:35]=[C:34]([NH2:33])[C:43]=2[N:44]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)(O)Cn1c(CO)nc2c(N)nc3ccccc3c21
Reactant: CC(C)[C@H](N)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Agent: CS(=O)(=O)NCCCCn1c(CO)nc2c(N)nc3ccccc3c21
Product: CC(C)[C@H](N)C(=O)OCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O

Procedure:
[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl L-valinate was prepared according to the general method used to prepare (4-amino-1-{4-{(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-2-yl)methyl L-valinate using 1-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol in lieu of N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide. The product was provided as off-white needles, mp 190-192° C.; MS (ESI) m/z 386 (M+H); Anal. Calcd for C20H27N5O3: C, 62.32; H, 7.06; N, 18.17. Found C, 62.08; H, 7.11; N, 17.96.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1.[OH:17]O>CC(O)=O>[Br:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][C:3]=1[S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)=[O:17]
Reactant: OO
Reactant: N#Cc1cc(Sc2cccc(Br)c2)c(Br)s1
Solvent: CC(=O)O
Product: N#Cc1cc(S(=O)c2cccc(Br)c2)c(Br)s1
Temperature: 50 °C

Procedure:
To a solution of 5-Bromo-4-(3-bromo-phenylsulfanyl)-thiophene-2-carbonitrile (Example 25: step g; 292 mg, 0.78 mmol) in AcOH (3 mL), 30% H2O2 (85 μL, 0.94 mmol) was added slowly and warmed to 50° C. for 2 hours. The reaction was concentrated and then dissolved in EtOAc and washed with water. The organic layer was dried (MgSO4) and concentrated. The compound was used without further purification. 1H-NMR (CDCl3): δ 7.87-7.85 (1H, m), 7.64 (2H, t, J=10.1, Hz), 7.57 (1H, s), 7.41 (1H, t, 7.91 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:18].[OH-]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([NH2:18])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)CCNC(=O)OCc1ccccc1

Procedure:
Crude 2-(N-benzyloxycarbonylamino)ethanesulfonyl chloride was dissolved in acetonitrile (10 mL). The resulting solution was cooled on an ice/water bath and a solution 1:1 of 28% NH4OH (5 mL) and acetonitrile (5 mL) was dropped therein. After stirring for 30′, the solvents were evaporated off under vacuum and the crude residue was recrystallised with methanol to give 2-(N-benzyloxycarbonylamino)ethanesulfonamide as white powder (0.51 g; 1.96 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10]1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](=[N:18][OH:19])[CH3:15])=[CH:10]1
Reactant: NO
Reactant: CC(=O)c1ccn(-c2c(C)cccc2C)c1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=NO)c1ccn(-c2c(C)cccc2C)c1

Procedure:
A mixture of 1-(2,6-dimethylphenyl)-3-acetyl-1H-pyrrole (20.0 g), hydroxylamine hydrochloride (25.0 g), pyridine (130 ml) in 100 ml of methanol is heated under reflux for 20 hours. Workup in the usual manner yields 1-(2,6-dimethylphenyl)-3-acetyl-1H-pyrrole oxime.
Reaction SMILES: BrC1[CH:3]=[N:4]C=C(Cl)C=1C=O.S1C=CN=C1S.[Cl:17][C:18]1C=N[CH:21]=[C:22]([S:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:23]=1[CH:24]=[O:25]>ClC1C=C(Cl)C=CN=1>[Cl:17][C:18]1[C:23]([CH:24]=[O:25])=[C:22]([S:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[CH:21]=[CH:3][N:4]=1
Reactant: O=Cc1c(Cl)cncc1Sc1nccs1
Reactant: O=Cc1c(Cl)cncc1Br
Agent: Clc1ccnc(Cl)c1
Agent: Sc1nccs1
Product: O=Cc1c(Sc2nccs2)ccnc1Cl

Procedure:
Introduction of the formyl group in 2,4-dichloro-pyridine according to the synthesis of 3-bromo-5-chloro-pyridine-4-carbaldehyde and subsequent reaction with thiazole-2-thiol according to the synthesis of 3-chloro-5-(thiazol-2-ylsulfanyl)-pyridine-4-carbaldehyde yielded the title compound. MS (m/z): 257.2 [H+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[N:6][CH:7]=1.[CH2:19](C([Sn])=C(CCCC)CCCC)[CH2:20]CC.C(OCC)(=O)C>CN(C=O)C>[CH:19]([C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[N:6][CH:7]=1)=[CH2:20]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(Br)cnn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 90.8 %

Procedure:
5-Bromo-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (2.0 g, 0.0066 mole), tributylvinyltin (2.3 g, 0.00726 mole) and Pd(PhCH2)Cl(Ph3P)2 (0.1 g, 0.000132 mole) were heated at 100° C. in DMF (75 mL) for 1 hour. The mixture was then poured into ethyl acetate and extracted 2×200 mL with aqueous KF, brine, dried (MgSO4), filtered through a pad of silica gel with ethyl acetate and evaporated in vacuo. The crude oil was purified by silica gel chromatography to give 5-ethenyl-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (1.62 g, 91% yield) as an off-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:2]1.[N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[N:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1CN[C@@H](C(O)=O)C1.[BH4-].[Na+]>CC#N.C(O)C>[OH:10][CH2:9][C@@H:8]([N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1
Reactant: O=CCCC1CCCOC1
Reactant: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C(O)[C@H]1CCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: O=C(NN(C(=O)OCc1ccccc1)[C@H](CO)CC1CCCOC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
To a stirred solution of 3-(tetrahydro-2H-pyran-3-yl)propanal (8.25 g, 0.058 mol) and dibenzyl azodicarboxylate (94%, 12.3 g, 0.041 mol) in MeCN (250 mL) at 0° C. was added (R-proline) (0.47 g, 0.0041 mol). After stirring the mixture at 0° C. for 15 hr. ethanol (100 mL) and NaBH4 (1.56 g, 0.041 mol) was added, and the mixture was stirred at 0° C. for 40 min. The reaction was quenched by slow addition of 10% aqueous citric acid (15 ml), and the whole solution was concentrated in vacuo. This residue was diluted with EtOAc (200 ml), washed with saturated brine (1×50 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give dibenzyl 1-((2S)-1-hydroxy-3-(tetrahydro-2H-pyran-3-yl)propan-2-yl)hydrazine-1,2-dicarboxylate (14.68 g, 81%).
Reaction SMILES: Cl[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.[B:21]1([OH:31])[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[CH2:23][O:22]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[OH:31][B:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C:2]3[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=3)=[CH:29][C:24]=2[CH2:23][O:22]1
Reactant: CC(C)OCCOc1nc(Cl)c(C(F)(F)F)cc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)c(C(F)(F)F)cc1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A mixture of 6-chloro-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinonitrile (180 mg, 0.58 mmol), benzo[c][1,2]oxaborole-1,5(3H)-diol (87 mg, 0.58 mmol) and Cs2CO3 (228 mg, 0.7 mmol) in DMSO (20 mL) was stirred at 40° C. for 1 hr, the mixture was diluted by water, extracted by EtOAc, the organic layer was concentrated in vacuo and the residue was purified by prep. HPLC (column: Gemini 100×21.2 mm, 5μ; liquid phase: [A-H2O; B—CH3CN+0.4% NH4OH] B %: 45%-65%, 15 min).to afford 6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(2-isopropoxyethoxy)-5-(trifluoromethyl)nicotinonitrile (170 mg, 69%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 9.24 (s, 1H), 8.73 (s, 1H), 7.79-7.77 (d, 1H), 7.31-7.31 (d, 1H), 7.23-7.21 (q, 1H), 4.97 (s, 2H), 4.14-4.11 (t, 2H), 3.47-3.45 (t, 2H), 3.43-3.37 (m, 1H), 0.98-0.96 (d, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]([C:15]([NH2:46])=[O:16])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:7][CH:8]=1)#[N:2]
Reactant: [NH4+]
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (intermediate 4, 25 mg, 45 μmol) in acetonitrile (1.0 mL) is treated with ammonium carbonate (9 mg, 90 μmol), and the mixture is stirred at room temperature for 30 min and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 3 mg; ESI mass spectrum [M+H]+=441; Retention time HPLC: 0.65 min (X018_S01).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(N(CC)CC)C>C(#N)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([O:17][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
The crude carboxylic acid is suspended in anhydrous acetonitrile (150 ml) and treated with p-nitrobenzyl bromide (7.56 g, 35 mμol) and triethylamine (4.9 ml, 35 mμol). The resulting solution is kept at room temperature for 2 days and then in a refrigerator for 3 days. The reddish orange solution is evaporated under vacuum and the residue shaken with ethyl acetate (100 ml, 2×50 ml) and filtered to remove triethylammonium bromide. The ethyl acetate filtrate is washed with water (3×100 ml) and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to an amber oil (13.62 g). Crystallization from diethyl ether affords N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]azetidin-2-one (6.84 g) as an off-white powder. Chromatography of the mother liquors on a silica gel column using 1:1 toluene-ethyl acetate as eluting solvent affords addition product (3.14 g) as an oil which solidifies.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[O:13][C:14]([CH3:43])([CH3:42])[C:15](=[O:41])[CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[C:8]([O:10]C)=[O:9])[N:6]=1.[OH-].[K+]>C(O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[O:13][C:14]([CH3:43])([CH3:42])[C:15](=[O:41])[CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: COC(=O)/C(=N\OC(C)(C)C(=O)C1CNCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(N)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)C1CNCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
(Z)-2-Amino-α-[[1,1-dimethyl-2-oxo-2-(N-tritylpiperazinyl)ethoxy]imino]-4-thiazoleacetic acid, methyl ester (4.03 g, 6.75 mmol) was suspended in a solution of 0.90 g of potassium hydroxide in ethanol (22.5 ml) and water (1.8 ml), and stirred overnight at room temperature. The reaction was then heated to 60° C. for 30 minutes. Upon cooling to room temperature, water (22.5 ml) was added, and the reaction mixture was filtered through Celite. The filtrate was then acidified to pH 3 with 1N hydrochloride acid while cooling in ice, and the precipitate that formed was isolated by filtration. The precipitate was washed with water, ether and acetonitrile to yield 1.71 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19]
Reactant: O=C(CBr)C1CCCCC1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)C2CCCCC2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromoacetylcyclohexane (Lotfield, Schaad, J. Am. Chem. Soc., 1954, 76, 35).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[CH:7]=1
Reactant: CCN(CC)CCN
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Product: CCN(CC)CCNc1cc(Cl)cc(NCCN(CC)CC)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added in small portions to 180 ml of N,N-diethylethylenediamine heated to 60° C., with stirring. Heating is continued for 30 minutes after the addition is complete. The reaction medium is diluted with 180 ml of ice-cold water. The product expected precipitates. It is drained, washed with water and then dried under vacuum at 60° C. in the presence of phosphorous pentoxide. After recrystallizing from 96° ethanol, it melts at 90° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[C:3]=1[OH:11].C(C1C=C(C=C(C)C=1O)[C:17]([NH:19][OH:20])=[NH:18])C>>[OH:11][C:3]1[C:4]([CH2:8][CH2:9][CH3:10])=[CH:5][C:6]([C:17]([NH:19][OH:20])=[NH:18])=[CH:7][C:2]=1[CH3:1]
Reactant: CCCc1cccc(C)c1O
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Product: CCCc1cc(C(=N)NO)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-methyl-6-propyl-phenol in analogy to literature procedures (e.g. B. Roth et al., J. Med. Chem. (1988), 31, 122-129; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine). LC-MS: tR=0.54 min; [M+1]+=209.43; 1H NMR (D6-DMSO): δ 0.90 (t, J=7.3 Hz, 3H), 1.48-1.59 (m, 3H), 2.19 (s, 3H), 2.56 (t, J=7.3 Hz, 2H), 7.37 (s, 1H), 7.40 (s, 1H), 9.34 (s, 1H).