Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:20](C1C=CC(CC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=[O:21].[N+](C1C=CC(C(C2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O>O.C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:20][OH:21])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C(=NO)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared by modification of procedures previously reported in the literature (Chapman and Fidler (1936) J. Chem. Soc, 448; Kulin and Leffek (1973) Can. J. Chem., 51: 687). A solution of chromic anhydride (20 g, 200 mmol) in 125 ml of H2O was added dropwise over 4 hours, to a suspension of bis(4-nitrophenyl)methane (25 g, 97 mmol) in 300 ml of acetic acid heated to reflux. The reaction mixture was heated at reflux for 1 hour, cooled to room temperature, and poured into water. The solid was collected by filtration, washed with H2O, 5% sodium bicarbonate, H2O, and air-dryed to provide a 1:1 mixture of bis(4-nitrophenyl)methane/4,4'-dinitrobenzophenone via 1H NMR. This material was oxidized with a second portion of chromic anhydride (20 g, 200 mmol), followed by an identical work-up procedure to provide the crude product. Trituration with 200 ml of benzene heated to reflux for 16 hours provided 4,4'-dinitrobenzophenone (20.8 g, 79%) as a yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1.C=O.[C:37]([BH3-])#N.[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[N:24]([CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH3:37])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1cccc(NC(=O)NC[C@@H]2CCCC[C@H]2NCCCc2ccc(F)cc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(CCCc1ccc(F)cc1)[C@@H]1CCCC[C@H]1CNC(=O)Nc1cccc(-c2nnnn2C)c1
Reaction time: 0.25 h

Procedure:
To a solution of N-[3-(1-methyl-tetrazol-5-yl)phenyl]-N′-[(1S,2R)-2-[3-(4-fluorophenyl)propylamino]-cyclohexylmethyl]urea (98 mg), the product of Step g of Example 31, in 4 mL of CH2Cl2 was added a solution of formaldehyde in THF (excess), and the mixture was stirred for 15 minutes. Then excess amount of sodium cyanoborohydride was added, and the mixture was continued to stir for 5 hrs at room temperature. After quenching the reaction with saturated Na2CO3, it was extracted with CH2Cl2. The extract was washed with water, dried over MgSO4 and evaporated to give an oily residue. It was purified by column chromatography (silica gel, 0.6:5.494 cNH4OH/CH3OH/CH2Cl2) to give pure N-[3-(1-methyl-tetrazol-5-yl)phenyl]-N′-[(1S,2R)-2-[N-methyl-3-(4-fluorophenyl)propylamino]-cyclohexylmethyl]urea.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[C:25]1(=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCCCC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=C1CCCCC1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.054 g, 0.15 mmol) was reacted with cyclohexanone (0.44 g, 4.5 mmol) in N,N-dimethylacetamide (1mL) in a sealed tube at 135° C. for 45 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C1CCCCC1.CCOC(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1ccc(Br)c[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Yield: 69.2 %

Procedure:
According to Scheme 5 Step 1: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 17.2 mmol, 3.00 g, Example 1 Step 1) and 4-methoxyphenylboronic acid (1.5 eq, 25.9 mmol, 3.93 g) according to the procedure described for Example 2 Step 2. Reaction conditions: 4.5 hours at 120° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 70 g SiO2) using pure AcOEt then AcOEt/MeOH 95/5 as eluent to afford 5-(4-methoxyphenyl)-(1H)-pyridin-2-one (11.9 mmol, 2.40 g, 69%) as a white solid.
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]2=[S:17])[CH:7]=[CH:8][C:9]=1[F:10]>C(#N)C.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:11]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]=[C:12]2[S:17][CH3:1])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=S
Reactant: CI
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCN=C1SC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.520 ml,) was added to a mixture of ethyl 3-(3,4-difluorophenyl)-2-thioxopiperidine-3-carboxylate (500 mg) in acetonitrile (5 mL) at room temperature, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (530 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[C@@H:42](O)[CH2:41]2>C(#N)C>[N:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[C@@H:42]([O:13][C:12](=[O:14])[CH:11]([NH:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([F:2])[CH:4]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:41]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1ccc(NC(C(=O)O)c2ccccc2)cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
(3-Fluoro-4-methyl-phenylamino)-phenyl-acetic acid hydrochloride (I48) (250 mg, 0.84 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (321 mg, 0.84 mmol), and HOBT (129 mg, 0.84 mmol) are dissolved in acetonitrile (6 mL). DIPEA (0.29 mL, 1.69 mmol) is added, followed by (R)-quinuclidin-3-ol (215 mg, 1.69 mmol) and the resulting yellow solution is stirred at RT overnight (Conversion complete by UPLC/MS-UV). MeCN is evaporated, the residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated. The crude compound is purified by filtration through a pad of silica using DCM/MeOH=9/1 as the eluent to obtain the title compound as a yellow oil (311 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[C:16]2[C:12]=1[CH2:13][C:14](=[N:24]O)[C:15]2=[O:23].C(N(CC)CC)C>ClCCl>[CH3:10][C:11]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[C:16]2[C:12]=1[CH2:13][CH:14]([NH:24][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:15]2=[O:23]
Reactant: Cc1c(C)c(C)c2c(c1C)CC(=NO)C2=O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C)c(C)c2c(c1C)CC(NC(=O)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Benzoyl chloride (1.635 g) is added dropwise to 4,5,6,7-tetramethyl-indan-1,2-dione 2-oxime (2.53 g) and triethylamine (2.25 g) in anhydrous dichloromethane (60 ml) at 0° C. The reaction mixture is stirred at room temperature for 1.5 hours after which the solid product is filtered off and allowed to stir with water (150 ml), refiltered and dried. The organic filtrate is washed with 1M HCl, 10% brine, saturated sodium bicarbonate solution, 10% brine and treated with magnesium sulphate. After filtration, the solvent is removed in vacuo and the product triterated with diethyl ether, filtered and dried.
Reaction SMILES: [C:1]1([S:7]([CH3:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:16]Br>C(#N)C>[C:1]1([S:7]([CH2:9][Br:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: CS(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(CBr)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Methyl phenyl sulfoxide (21.644 g, 154.4 mmol) was dissolved in anhydrous pyridine (27.4 mL, 2.2 eq) and dry acetonitrile (100 mL). The solution was cooled to −40° C. under an argon atmosphere. A solution of bromine (49.4 g, 2 eq) in dry acetonitrile (50 mL) was added slowly, maintaining the same temperature. The mixture was stirred at −40° C. for 1 h and then overnight at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in dichloromethane. The organic layer was washed with Na2S2O3 20%, dried over anhydrous Na2SO4 and concentrated to dryness.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47].C(N(CC)CC)C>ClCCl>[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH:47][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH:6]([CH:4]2[CH2:3][C:2]([CH3:1])([CH3:28])[CH2:5]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:8][CH:9]=1
Reactant: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1

Procedure:
(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (Intermediate 26, 1.0 eq.), 1-hydrobenzotriazole hydrate (1.2 eq.), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 eq.), beta-alanine methyl ester hydrochloride (1.1 eq.), and triethylamine (1.3 eq.) were combined in anhydrous dichloromethane in a similar manner as described in the experimental for intermediate 27 to provide (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester which was resolved via chiral chromatography to provide the title compound. Preparative chiral SFC: (Chiralpak AD-H column, 21 mm×25 cm, 40% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier, 65.0 mL/min flow rate, 2.71 retention time); 1H NMR (400 MHz, CDCl3) δ 7.63-7.69 (m, 2H), 7.58 (t, J=3.9 Hz, 2H), 7.45-7.51 (m, 3H), 7.41 (ddd, J=8.4, 7.0, 1.6 Hz, 1H), 7.14 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 6.72 (t, J=6.0 Hz, 1H), 5.31 (dd, J=9.7, 6.7 Hz, 1H), 4.75 (d, J=6.8 Hz, 1H), 3.69 (q, J=6.2 Hz, 5H), 2.55-2.71 (m, 3H), 2.28 (d, J=0.8 Hz, 3H), 1.95 (ddd, J=11.2, 8.0, 3.0 Hz, 1H), 1.78 (dd, J=11.1, 9.0 Hz, 1H), 1.64-1.72 (m, 2H), 1.15 (s, 3H), 1.08 (s, 3H); MS (M+1): 460.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1.[C@@H:22]12[C:31](=O)[O:30][C:28](=[O:29])[C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27]2.[ClH:33]>N1C=CC=CC=1.C(O)C>[ClH:33].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]4[C:28](=[O:29])[C@H:23]5[C@H:22]([CH2:27][CH2:26][CH2:25][CH2:24]5)[C:31]4=[O:30])[CH2:7][CH2:8]3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), then was treated with HCl in ethanol (45 ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p.=229°-231° C. ANALYSIS: Calculated for C24H30FN3O3.HCl: 62.13%C 6.73%H 9.06%N Found: 61.79%C 6.68%H 8.92%N
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([C:26]([OH:28])=O)[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:28])[CH:18]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1cccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c1
Yield: 72.1 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) benzene-1,3-dioic acid afforded, after flash chromatography (EtOAc), 4.68 g (72%) of the title compound as a yellow oil. MS m/e (%): 558 (M+NH4+, 100), 541 (M+H+, 90).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:12]1[C:13](Cl)=[C:14]([Cl:24])[C:15]2[O:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17][C:16]=2[CH:23]=1)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:24][C:14]1[C:13]2[O:3][N:2]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:12]=2[CH:23]=[C:16]2[CH2:17][CH:18]([C:20]([OH:22])=[O:21])[O:19][C:15]=12
Reactant: NO
Reactant: O=C(c1ccccc1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2cc3c(-c4ccccc4)noc3c(Cl)c2O1
Reaction time: 48 h
Yield: 32.3 %

Procedure:
Hydroxylamine hydrochloride (15.19 g, 0.2186 mol.) and (3a) (10.84 g., 0.0322 mol.) were heated at reflux in 75 ml. of dry pyridine for 5 hours. On cooling, the pyridine was removed on a rotary evaporator and chased with ethanol. The residue, a yellow gum, was taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid and brine, then dried over anhydrous magnesium sulfate and evaporated to a gum containing both E and Z isomers of the oxime. Without further purification, the gum was taken up in 20 ml. of absolute ethanol and treated with 120 ml. of 1M alcoholic potassium hydroxide at reflux on a steam bath for 3 hours then refrigerated at 0°-5° C. for 48 hours. The resulting precipitate was collected by filtration, washed with hexane, dried, and dissolved in 300 ml. warm distilled water. Acidification to pH 2.0 by addition of 4.0 M aqueous hydrochloric acid gave a gelatinous precipitate which was extracted into ethyl acetate, dried with anhydrous magnesium sulfate, decolorized with Darco, and evaporated. Recrystallization from ethyl acetate with hexane afforded the furobenzisoxazole (4a) in 32.3% yield, m.p. 214°-215° C. Analysis (C16H10ClNO4) C,H,N,Cl.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23][C:22]1=[O:31].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:21][C:22](=[O:31])[CH2:23]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: O=C1CNc2ccccc2N1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(=O)Nc2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (105 mg) and 3,4-dihydro-1H-quinoxalin-2-one (R. E. TenBrink et al., J. Med. Chem., 1994, 37, pp. 758-768) (267 mg) in dimethylformamide (0.75 mL) was heated at 140° C. for 45 hours. The resulting mixture was poured into water and extracted twice with diethyl ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 30% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (67.8 mg), m.p. 69° C.-71° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](I)[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[S:11]([CH3:14])(=[O:12])=[O:13])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Nc1cnccc1C1CC1
Reactant: CC(C)CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCN(c1cnccc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
A suspension of Example 17F (814 mg, 3.83 mmol) and cesium carbonate (1.87 g, 5.75 mmol) in N,N-dimethylformamide was treated with isoamyl iodide (555 μL, 835 mg, 4.22 mmol) followed by stirring at room temperature for 48 hours. The mixture was diluted with ethyl acetate and extracted with water (3×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded an amber oil, which was chromatographed over a 50 g silica gel cartridge, eluting with 15-70% ethyl acetate in dichloromethane. These procedures afforded the product (474 mg, 44%) as an off-white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([C:15](=[O:18])[NH:16][CH3:17])[C:13]=1[I:14])[C:8](N)=[O:9])=[O:4].N([O-])=[O:22].[Na+].O>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][NH:2][C:3]([C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([C:15](=[O:18])[NH:16][CH3:17])[C:13]=1[I:14])[C:8]([OH:22])=[O:9])=[O:4]
Reactant: CNC(=O)c1c(I)c(C(N)=O)c(I)c(C(=O)NC)c1I
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1c(I)c(C(=O)O)c(I)c(C(=O)NC)c1I
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
12.3 g of 3,5-bis(N-methylcarbamoyl)-2,4,6-triiodobenzoic acid amide is suspended in 80 ml of glacial acetic acid. Under agitation, a mixture of 1.66 g of sodium nitrite in 12 ml of concentrated sulfuric acid (prepared under ice cooling) is added in small portions at room temperature; during this step the temperature rises from 24° C. to 42° C. The mixture is then stirred for 3 hours at room temperature, 30 minutes at 50° C., and 90 minutes at 70° C. After agitating overnight at room temperature, the reaction mixture is stirred into 400 ml of water. The precipitate is vacuum-filtered after 4 hours, washed with water, and dried at 50° C. under vacuum. The crude product (11.9 g) is dissolved in 110 ml of water and 12 ml of 2 N sodium hydroxide solution, adjusted to pH 6.5 with 2 N acetic acid, and stirred for 30 minutes with 1 g of carbon. After the carbon has been removed by vacuum-filtering, the solution is precipitated with 16 ml of 2 N hydrochloric acid. After vacuum-filtering and drying at 50° C. under vacuum, 10.7 g (87% of theory) of 3,5-bis(N-methylcarbamoyl)-2,4,6-triiodobenzoic acid is obtained, mp>300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:16](Cl)=[CH:15][C:13]([NH2:14])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:9][C:10]1[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][C:13]([NH2:14])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(F)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of 4-fluorophenol (1.63 g, 14.54 mmol) in DMSO (20 ml) was added 4,5-dichloro-2-nitroaniline (3 g, 14.49 mmol) and potassium carbonate (4 g, 28.94 mmol) with stirring overnight at 90° C. The reaction was then quenched by the addition of water (200 ml), extracted with ethyl acetate (3×100 ml) and dried over anhydrous magnesium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluorophenoxy)-2-nitroaniline as a yellow solid (2.0 g, 49%). Next, to a solution of 4-chloro-5-(4-fluorophenoxy)-2-nitroaniline (2 g, 7.08 mmol) and hydrogen chloride (1.8 ml) and ethanol (25 ml) was added Zn powder (2.8 g) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. and then concentrated under vacuum. The residue was dissolved in water (300 ml), pH adjusted to 8 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×80 ml). The combined organic layers were dried and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluorophenoxy)benzene-1,2-diamine as red oil (1 g, 83%). Finally, a solution of 4-chloro-5-(4-fluorophenoxy)benzene-1,2-diamine (400 mg, 1.58 mmol) in 2,2-difluoro-3,3-dimethylbutanoic acid (4 ml) was stirred overnight at 95° C. in an oil bath. Then the solution was poured into water (100 ml), adjusted to pH 8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenoxy)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (19.9 mg, 3%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1.C(OC(N1CCC2NN(C3CCC(C)CC3)C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CC1CCC(Br)CC1
Agent: CC1CCC(N2NC3=C(CCN(C(=O)OC(C)(C)C)CC3)C2c2ccc(Cl)cc2)CC1
Product: CC1CCC(n2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)CC1
Yield: 10.7 %

Procedure:
The title compound (11 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.30 mmol) using 1-bromo-4-methyl-cyclohexane (1.0 mmol) in place of chloro-cyclobutane. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(4-methyl-cyclohexyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H26ClN3, 343.18; found, m/z 344.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.34 (m, 4H), 4.10-4.06 (m, 1H), 3.39-3.37 (m, 2H), 3.28-3.26 (m, 2H), 3.17-3.15 (m, 2H), 2.94-2.91 (m, 2H), 1.96-1.89 (m, 2H), 1.83-1.76 (m, 4H), 1.52-1.10 (m, 2H), 0.91-0.87 (m, 4H).