Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](=[N:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.C(O[C:26](=[O:30])[CH2:27][C:28]#[N:29])C.C([O-])(=O)C.[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:10]([CH3:11])=[C:27]([C:28]#[N:29])[C:26](=[O:30])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(NN=C(Sc2ccc(Cl)cc2)C(C)=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(Sc3ccc(Cl)cc3)c(C)c(C#N)c2=O)cc1
Temperature: 160 °C

Procedure:
A flasked equiped with a claisen distillation head and magnetic stirring was charged with mixture of 32.6 g (0.097 mole) 1-[(4-chlorophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, 24.8 ml of ethylcyanoacetate and 12.2 g of ammonium acetate. The mixture was heated under a nitrogen atmosphere at 160° C. for 30 min. The reaction mixture was cooled and dissolved in methylene chloride. The organic layer was washed successively with sat'd aqueous sodium bicarbonate and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to yield semi pure product. The residue was recrystallized from 1900 ml of ethanol to yield 33.05 g of 6-[(4-chlorophenyl)thio]-2,3-dihydro-2-(4-methoxyphenyl)-5-methyl-3-oxo-4-pyridazinecarbonitrile, mp 146°-148° C. (EtOH).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42]([OH:44])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:46][NH2:47]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42](=[O:44])[NH:47][CH3:46])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN
Agent: Cl
Product: CNC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1C(=O)OCc1ccccc1

Procedure:
According to general procedure D, 0.05 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1,2-dicarboxylic acid 1-benzyl ester (from example 3b) and methylamine-hydrochloride are used to afford the title compound as a yellow oil. Rf=0.50 (dichlormethane-methanol 9:1); Rt=4.52.
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16]C(=O)C4C=CC=CC=4C(F)(F)F)[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4]CC1.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].[CH2:39]([Mg]Br)C(C)C>>[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:16][C:13]1[CH:14]=[CH:15][C:7]2[CH:6]([CH2:1][CH:5]([CH3:4])[CH3:39])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=1)=[O:33]
Reactant: CC(C)C[Mg]Br
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1Cl
Product: CC(C)CC1OB(O)c2cc(NC(=O)c3ccccc3Cl)ccc21

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with 2-chlorobenzoyl chloride replacing 2-trifluoromethylbenzoyl chloride, and with isobutyl magnesium bromide replacing cyclopentyl magnesium bromide. Data: LCMS (M/Z): 344 (M+H); 1H NMR (DMSO-d6) δ: 10.47 (s, 1H), 9.13 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.66 (dd, J=8.2, 2.0 Hz, 1H), 7.51-7.55 (m, 1H), 7.38-7.50 (m, 2H), 7.30 (d, J=8.2 Hz, 1H), 5.10 (dd, J=9.8, 3.0 Hz, 1H), 1.79-1.92 (m, 1H), 1.65 (ddd, J=13.8, 9.0, 3.1 Hz, 1H), 1.26 (ddd, J=14.0, 9.7, 4.7 Hz, 1H), 0.98 (d, J=6.5 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[N:26]1([C:8]([C:7]2[CH:6]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:13]=[CH:12][CH:11]=2)=[O:10])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(C(=O)N2CCOCC2)c1
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of 3-(aminosulfonyl)benzoic acid (6 g, 0.029 mol) in THF (100 ml) at 0° C. is added CDI (5.8 g, 0.035 mol) and the mixture is stirred for 4 h. To this mixture morpholine (7.8 ml, 0.089 mol) is added dropwise and the mixture is stirred at room temperature for 15 h. The solvent is removed under vacuum and the residue is diluted with EtOAc (100 ml), washed with a 10% solution of sodium bicarbonate, water and brine. The solvent is removed under vacuum and the residue is taken up with small amount of water (15 ml) and stirred for 15 min. The solid is collected by filtration to afford 4 g (50%) of the title compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.88-7.90 (1H, m), 7.83 (1H, s), 7.64-7.65 (2H, m), 7.47 (2H, bs), 3.56-3.64 (6H, m), 3.28-3.34 (2H, m); HPLC (Max polt) 98%, Rt, 4.09 min; LCMS: (ES+): 206.2.
Reaction SMILES: O=C(Cl)[O:3][C:4]([Cl:7])(Cl)[Cl:5].Cl.Cl.[Cl:11][CH2:12][CH2:13][N:14]([CH2:22][CH2:23][Cl:24])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.CCN(CC)CC>CCl.C1COCC1>[ClH:5].[Cl:11][CH2:12][CH2:13][N:14]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:4]([Cl:7])=[O:3])=[CH:19][CH:20]=1)[CH2:22][CH2:23][Cl:24]
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)Nc1ccc(N(CCCl)CCCl)cc1
Reaction time: 0.5 h

Procedure:
A solution of diphosgene (197 mg, 1.2 mmol.) in dry CH3Cl was added dropwise to a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (37) (0.306 g, 1.0 mmol) in dry THF (25 mL) containing Et3N (0.5 mL) in an ice bath with vigorous stirring for 30 min. It formed crude p-[(N,N-bis(2-chloroethyl)amino)]phenylcarbamoyl chloride hydrochloride (38). The reaction mixture was filtered through a pad of Celite and washed with THF (5 mL). The filtrate and washings were combined and was then added dropwise into a solution of 3-amino-5-(4-methylacridin-9-ylamino)phenyl]-methanol18 (0.329 mg, 1.0 mmol) in dry DMF (20 mL) containing Et3N (0.5 mL) at 0° C. and stirred at room temperature for 16 h. The solvent was removed by distillation under reduced pressure to dryness and the residue was dissolved in CHCl3/MeOH and mixed with silica gel (5 g) and then evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (2×20 cm) and chromatographed using CHCl3/MeOH (100:2 v/v) as eluent. The fractions containing the main product were combined and concentrated in vacuo and the residue was recrystallized from CHCl3/MeOH to give 1-{4-[bis(2-chloroethyl)amino]phenyl}-3-[3-hydroxymethyl-5-(4-methylacridin-9-ylamino)phenyl]urea (16, BO-1050), 179 mg (30%); mp 251-252° C.; 1H NMR (DMSO-d6) δ 3.64-3.71 (8H, m, 4×CH2), 4.00 (3H, s, Me), 4.47 (2H, d, J=5.1 Hz, CH2) 5.11 (1H, t, J=5.1 Hz, exchangeable, OH), 6.35 (1H, s, ArH), 6.68 (2H, d, J=8.8 Hz, 2×ArH) 6.75 (1H, s, ArH), 6.88-7.18 (4H, m, 4×Ar H), 7.24 (2H, d, J=8.8 Hz, 2×ArH) 7.52 (2H, s, 2×ArH), 7.83 (2H, s, 2×Ar H), 8.25 (1H, s, ArH) 8.40 (1H, s, ArH), 10.24 (1H, s, exchangeable, NH). Anal. Calcld. for (C32H31Cl2N5O2.3H2O): C, 59.81; H, 5.80; N, 10.89. Found: C, 59.74; H, 5.79; N, 9.67.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:14])[CH:3]=1.[CH3:37][O:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][C:41]=1[N+:50]([O-:52])=[O:51].N1C=CC=CC=1.C(O)(=O)C>C(Cl)Cl>[C:32]([C:22]1[CH:23]=[C:24]([C:27]([CH2:30][CH3:31])([CH3:28])[CH3:29])[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13]([C:4]1[CH:3]=[C:2]([NH:1][S:46]([C:43]2[CH:44]=[CH:45][C:40]([C:39]([O:38][CH3:37])=[O:53])=[C:41]([N+:50]([O-:52])=[O:51])[CH:42]=2)(=[O:47])=[O:48])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12])=[O:14])([CH2:35][CH3:36])([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(NS(=O)(=O)c3ccc(C(=O)OC)c([N+](=O)[O-])c3)c3ccccc3c2O)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Amino-N-[4-(2,4-di-t-pentylphenoxy)butyl]-1-hydroxy-2-naphthamide (11.7 g, 23.8 mmoles) was dissolved in methylene chloride (300 ml) under nitrogen and reacted with intermediate (B) (6.7 g, 25.2 mmoles) in the presence of pyridine (2.0 g). After 5 hours of stirring at room temperature, acetic acid (2 ml) was added and the mixture was evaporated to dryness. Trituration of the residue gave a solid which was collected by filtration and recrystallized from ethanol; yield, 8.0 g (46.8 percent).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][O:8][C:9]([O:19][CH3:20])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.O>O1CCCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:7][O:8][C:9]([C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:1][CH3:2])([O:19][CH3:20])[CH3:18]
Reactant: COC(C)(OC)C(=O)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC=C(c1ccccc1)C(C)(OC)OC
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
At 5° C., a solution of 2.5 g of potassium tert-butoxide in 25 ml of tetrahydrofuran (THF) was added dropwise to 8.2 g of ethyltriphenylphosphonium bromide dissolved in 50 ml of THF. The mixture was then stirred at 5° C. for about 10 min, and a solution of 3.9 g of 2,2-dimethoxy-1-phenylpropan-1-one from Example 1 in 10 ml of THF was added dropwise. The reaction mixture was stirred at 20 to 25° C. for 72 h and then admixed with about 300 ml of water and extracted with methyl tert-butyl ether (MTBE). The organic phases were washed with water, dried and freed of the solvent. Silica gel chromatography (MTBE/cyclohexane 1:10) of the residue gave 2.2 g of product as an isomer mixture which can be further reacted without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:34])(=[N:27][C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[O:26])=[CH:21][CH:20]=1>>[CH:30]([NH:29][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:34])=[O:26])=[O:33])([CH3:32])[CH3:31]
Reactant: CC(C)NC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CC(C)NC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 39 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (291.7 mg, 1.08 mmol) with (RS)—S-(4-aminophenyl)-N-(isopropylcarbamoyl)-S-methylsulphoximide (251 mg, 0.98 mmol) according to procedure 5c, the desired product is obtained in 39% yield (186 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:27])([F:26])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:22]([F:27])([F:26])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 150 °C
Yield: 59.8 %

Procedure:
A mixture of 1.00 g of 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester, 0.84 g of potassium trifluoroacetate, 1.18 g of cuprous iodide, 4 ml of toluene and 10 ml of N,N-dimethylformamide was stirred with heating at 150° C. for 5.5 hours under a nitrogen gas atmosphere while removing toluene. The reaction mixture was combined with a mixture of 2N hydrochloric acid and ethyl acetate, and unsoluble matters were filtered out with Celite. Organic layers were collected from the filtrate and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated saline, dried over sodium sulfate, then concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography (eluent: ethyl acetate:hexane=10:1) to give 0.51 g of 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester as an oil;
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C([C:10]1[CH:14]=[CH:13][N:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:11]=1C)(O)=O>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[CH:10]=[CH:11][N:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:13]=1[CH3:14])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C(=O)O)ccn1-c1ccc2ccccc2n1
Solvent: ClCCl
Product: Cc1c(C(=O)Cl)ccn1-c1ccc2ccccc2n1
Product: Cl
Temperature: 20 °C
Reaction time: 16 h
Yield: 104.2 %

Procedure:
10 mL (114.2 mmol) of oxalyl chloride are added at 20° C. under an argon atmosphere to 1.8 g (6.25 mmol) of 3-carboxy-2-methyl-1-(quinol-2-yl)-1H-pyrrole dissolved in 120 mL of dichloromethane. After stirring at 20° C. for 16 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 2 g of 3-chlorocarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole hydrochloride in the form of a beige-coloured solid which is used directly in the following step.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6].Cl[C:26]1[N:27]=[CH:28][C:29]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:24][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:22]=[C:21]([CH:20]=[C:10]([C:11](=[O:12])[NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[CH:9]=1)[O:23][C:26]1[N:27]=[CH:28][C:29]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[N:30][CH:31]=1)[CH3:6]
Reactant: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 36.6 %

Procedure:
A mixture of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazol-3-yl)benzamide (0.1 g, 0.29 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (66 mg, 0.35 mmol) and potassium carbonate (81 mg, 0.59 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 6 hours. The resulting mixture was reduced in vacuo and ethyl acetate (50 mL) added. The organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The residue was chromatographed on silica, eluting with 10-100% ethyl acetate in isohexane to give the desired compound (52 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([NH2:8])=[NH:7].[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[F:20].CN1CCOCC1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:7][C:6](=[NH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([F:2])[CH:4]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Cc1ccc(C(=N)N)cc1F
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=N)NS(=O)(=O)c2ccc(F)c(Cl)c2)cc1F
Yield: 35.8 %

Procedure:
Add 3-fluoro-4-methylbenzamidine hydrochloride (0.025 g, 0.133 mmol) in THF (0.5 mL) to 3-chloro-4-fluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol) followed by N-methylmorpholine (0.2 mL). The reaction mixture was concentrated and chromatographed using reverse phase chromatography (gradient of 5–95% (0.1% TFA in CH3CN) in (0.1% TFA in H2O). A white solid (16.4 mg, 36%) was isolated. ES Positive Ion MS [M+H]+ ions observed: m/z 345 (35Cl) and m/z 347 (37Cl).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13](C)=[C:14]([C:27]([O:29][CH3:30])=[O:28])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:30][O:29][C:27](=[O:28])[C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 62.8 %

Procedure:
1.58 grams of 80 percent pyridinium bromide perbromide (3.95 millimoles) was added in one portion to a cooled to 0° C. solution of 1.00 gram (3.32 millimoles) of dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.4 milliliter of pyridine in 20 milliliters of dry ethanol-free chloroform. The resulting mixture was stirred for 45 minutes at 0° C. and then heated at reflux temperature for 1.3 hous. Thereafter, the mixture was cooled to room temperature, diluted with chloroform and the resulting solution washed successively with 2N hydrochloric acid and brine, dried over magnesium sulfate, and dried solution filtered to remove the drying agent, and then subjected to reduce pressure to vaporize the solvent and to recover as residue 1.41 grams of product as a yellow oil. The oil was chromatographed on silica gel using 70 percent ethyl acetate--30 percent hexane as eluant to obtain 595 milligrams (63 percent yield) of purified methyl 2-methyl-4-phenyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]-pyridine-3-carboxylate product which after recrystallization from ethyl acetate-hexane and drying at 60° C. at 0.005 millimeters mercury pressure for 17 hours had a melting point of 193°-196° C. Elemental analyses for the product were as follows:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.[CH2:18]([N:21]([CH2:29][C:30](N(OC)C)=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[CH2:20].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:18]([N:21]([CH2:29][C:30]([C:17]1[S:13][N:14]=[CH:15][CH:16]=1)=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:19]=[CH2:20]
Reactant: c1cnsc1
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN(CC(=O)c1ccns1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
To a −78° C. solution of diisopropylamine (9.01 mL, 64.01 mmol) in tetrahydrofuran (80 mL) is added n-butyl lithium (30.78 mL, 49.24 mmol, 1.6 M in hexanes) drop wise under nitrogen. The resulting solution is stirred at −78° C. for 20 minutes and then a solution of isothiazole (4.19 g, 49.24 mmol) in tetrahydrofuran (10 mL) is added drop wise. The resultant white slurry is stirred for 30 minutes at −78° C. A solution of tert-butyl N-allyl-N-[2-(methoxy(methyl)amino)-2-oxo-ethyl]carbamate (6.36 g, 24.62 mmol) in tetrahydrofuran (50 mL) is then added to the slurry over a 15 minutes period. The reaction is then stirred for 30 minutes at −78° C., warmed to ambient temperature and is stirred for 30 minutes. Saturated ammonium chloride (200 mL) is then added. The resulting solution is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product is purified over silica gel with a 35 minute, 5% to 100% ethyl acetate in hexanes gradient, to give the title compound (6.00 g, 21.25 mmol, 86%). ES/MS (m/e): 283.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:8])=[CH:3][CH2:4][C:5]([OH:7])=[O:6].N1(C2C=CN=CC=2)CCCC1.[O:20]([C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]O)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C>[O:20]([C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][O:6][C:5](=[O:7])[CH2:4][CH:3]=[C:2]([F:8])[F:1])=[CH:35][CH:36]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)CC=C(F)F
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOCC
Product: O=C(CC=C(F)F)OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of 3.0 g of 4,4-difluorobut-3-enoic acid in 50 ml of diethyl ether is treated with 0.36 g of 4-pyrrolidinopyridine and 5.66 g of 2-(4-phenoxyphenoxy)ethanol, and the mixture is cooled to 0° C. A total of 5.58 g of N,N'-dicyclohexylcarbodiimide are added in portions at a temperature of between 0° C. and +5° C., the ice-cooling is removed, and the reaction mixture is allowed to come to room temperature in the course of 16 hours, with stirring. The N,N'-dicyclohexylurea which has precipitated as a solid is separated off and discarded. The supematant solution is evaporated. The residue obtained is purified by column chromatography on silica gel (eluent: hexane/ethyl acetate, 9:1). This gives pure 2-(4-phenoxyphenoxy)ethyl 4,4-difilorobut-3-enoate in the form of an oil (refractive index nD23 : 1.5315).
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: CCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@H](Cc1ccccc1)C(=O)NO
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.