Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(OC(=O)C)(=O)C>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:2](=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])([CH3:4])[CH3:1]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)=C(C)C
Temperature: 90 °C
Yield: 32.3 %

Procedure:
Diethyl isopropylidenemalonate was prepared according to the procedure of E. L. Eliel, R. O. Hutchins, and Sr. M. Knoeber, Organic Synthesis Coll. Vol VI, 442, 1988, with following modifications. A mixture of acetone (54 g, 0.93 mol Mallinckrodt), diethyl malonate (100 g, 0.62 mol, Aldrich), acetic anhydride (81 g, 0.78 mol, Mallinckrodt), and zinc chloride (12.5 g, 0.78 mol, Aldrich) was refluxed (90° C. oil bath) for 18 h while protected from moisture. The reaction solution was diluted with dichloromethane (500 ml) and washed with cold water (3×50 ml). The aqueous washes were combined and extracted with dichloromethane. All dichloromethane layers were combined and concentrated by spin evaporation in vacuo. The residual oil was distilled under vacuum and the fractions boiling at 102-138° C. at 12 Torr were combined with the pot residue and heated for 6 h with a 200° C. oil bath. The dark oil was redistilled to give 40.1 g (32%) of diethyl isopropylidenemalonate as a clear oil, b.p., 110-115° C./12 mmHg:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:10][CH2:9][CH:8]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][CH2:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=43)=[N:13][N:12]=2)[CH2:7][CH2:6]1>ClCCl>[N:5]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:10][CH2:9][CH:8]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=43)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: c1ccc(N2CCC(c3nnc4n3-c3ccccc3CNC4)CC2)nc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1Cc2ccccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Acetyl chloride (22 mg, 0.29 mmol) was added to an ice cooled solution of the amine of example 1 (100 mg, 0.29 mmol) in dichloromethane (50 ml) and stirred at room temperature for 2 hours. The dichloromethane was evaporated off under reduced pressure and the residue purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant to give the title compound as a brown foam (102 mg).
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].N1C=CC=CC=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>C(Cl)Cl>[CH2:2]([O:5][NH:6][S:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:3]=[CH2:4]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C=CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a stirred solution of O-allylhydroxylamine hydrochloride (147.05 g, 1341.59 mmol) in DCM (2.5 L) at 0° C., pyridine (318 mL, 3948 mmol) was added followed by the addition of 2-nitrobenzene-1-sulfonyl chloride (250 g, 1128.05 mmol) portionwise as a solid. The reaction mixture was then stirred at the same temperature for 1 h. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with 1.5 N HCl (1 L). The organic layer was separated, washed with water (250 mL), brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield the residue. The crude was purified by crystallization using EtOAc:petroleum ether (1:3) (800 mL) and afforded 202 g of the title compound as a light brown solid. The mother liquor was concentrated and purified by silica gel column chromatography (mesh 60-120) using petroleum ether:EtOAc (7:3) to yield another 19.1 g of the title compound as a yellow solid. The total yield is 76%.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([CH:25]1[O:49][CH:26]1[CH2:27][O:28][CH2:29][CH:30]1O[CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]CCC)CCCCCCCCCCCCCCC>O1CCCC1>[CH2:1]([NH:8][CH2:25][CH:26]([OH:49])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCC1OC1COCC1OC1CCCCCCCCCCCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(O)CNCc1ccccc1

Procedure:
A mixture of 24.4 g of benzylamine, 100 cc. of tetrahydrofurane and 34 g of hexadecyl-2.3-epoxypropylether is refluxed for 8 hours and the solvent is evaporated in a vacuo. The residue is recrystallized from hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]2[CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH2:8][C:9]=2[C:10](=[O:14])[C:11]=1[O:12][CH3:13].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.C(N(CC)CC)C>[CH3:13][O:12][C:11]1[C:10](=[O:14])[C:9]2[CH2:8][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)=[O:26])=[CH:27][CH:28]=3)[CH2:6][C:5]=2[C:4](=[O:29])[C:3]=1[O:2][CH3:1]
Reactant: CN1CCNCC1
Reactant: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)O)cc3)C2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)N4CCN(C)CC4)cc3)C2)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 49.3 %

Procedure:
A mixture of 4-[4-(5,6-dimethoxy-4,7-dioxoindan-2-yl)butoxy]benzoic acid (500 mg), 1-methylpiperazine (250 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (479 mg), 1-hydroxybenzotriazole monohydrate (383 mg), triethylamine (0.697 ml), andTHF (20 ml) was stirred at room temperature for 10 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with recrystallization from ethyl acetate-diisopropylether to yield the entitled compound (297 mg) as crystals.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[NH:3]1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:24]2[CH:28]=[N:27][C:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([CH2:39][NH2:40])[CH:36]=[CH:35][N:34]=3)=[N:25]2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:40][CH2:39][C:37]2[CH:36]=[CH:35][N:34]=[C:33]([O:32][CH2:31][CH2:30][CH2:29][C:26]3[N:27]=[CH:28][NH:24][N:25]=3)[CH:38]=2)=[O:14])[NH:3]1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(NCc1ccnc(OCCCc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
A suspension of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (25.0 mg, 0.11 mmol), 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methanamine obtained in Reference Example 28 (28.0 mg, 0.069 mmol) and diisopropylethylamine (159 mg, 1.20 mmol) in ethanol (3 mL) was stirred at 80° C. for 15 hr. After cooling the mixture to room temperature, the resulting solid was collected by filtration, and washed with ethanol. 4N Hydrochloric acid and ethyl acetate were added to the crude crystals, and the mixture was stirred at room temperature for 2 hr. Water was added to the mixture, and the aqueous layer was weakly acidified with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (28.0 mg, 60%).
Reaction SMILES: C[O:2][C:3](=[O:32])[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]([CH2:30][CH3:31])[C:25](=[O:29])[CH2:26][O:27][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Li+].[OH-].Cl>C1COCC1>[CH2:30]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:6]=1)[C:25](=[O:29])[CH2:26][O:27][CH3:28])[CH3:31]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)COC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COC

Procedure:
(2′-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.135 g, 0.31 mmol) in THF (2 mL) was treated with 1N aqueous LiOH (2 mL) for 2 hours at room temperature. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH3:3][N:4]([C:16](=[O:18])[CH3:17])[C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN[C@@H](Cc1ccncc1)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(C)[C@@H](Cc1ccncc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Methyl-3-(4-pyridinyl)alanine, dihydrochloride (1.4 g, 0.0053 mol) is stirred in dry tetrahydrofuran (20 mL) with acetic anhydride (0.9 mL, 0.0095 mol) and triethylamine (3.3 mL, 0.0233 mol) at room temperature. After stirring at room temperature overnight the mixture is diluted with 20 mL tetrahydrofuran and filtered and the solids washed with tetrahydrofuran. The filtrate is concentrated to a dark oil, dissolved in dichloromethane (50 mL) and washed with dilute sodium bicarbonate solution (50 mL). The organic layer is dried over magnesium sulfate and concentrated. The residue is triturated with diethyl ether, filtered, and dried to afford 0.83 g of the title compound as a tan solid; mp 86-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].OS(O)(=O)=O.[CH3:17]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: COc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(OC)c1
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of 3-methoxybenzoic acid (20 g, 131.58 mmol, 1.00 equiv) in MeOH (100 mL) and H2SO4 (13 g, 130.00 mmol, 1.00 equiv, 98%) was allowed to react, with stirring in a 250-mL round-bottom flask, overnight under reflux. The reaction was quenched by the addition of 100 mL of water/ice, extracted with 3×100 mL of dichloromethane, and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum yielding 21 g (96%) of methyl 3-methoxybenzoate as yellow oil.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([F:19])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([N:16]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:14]([F:19])[CH:13]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: BrCCCCBr
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N1CCCC1

Procedure:
A mixture of 2.3 g (8.8 mmoles) of 4-(1-adamantyloxy)-2-fluoroaniline, 1.90 g (8.80 mmoles) of 1,4-dibromobutane, and 2.68 g (19.4 mmoles) of K2CO3 in deaerated absolute ethanol (25 ml) is refluxed for twenty-four hours. The solvent is evaporated, and the residue taken up in methylene chloride (125 ml) and water (125 ml). The methylene chloride layer is washed with 2×125 ml of water, and the combined aqueous portions are extracted with methylene chloride (50 ml). The combined methylene chloride layers are dried and concentrated. The crude product is chromatographed by high pressure liquid chromatography on a 2.54 × 109 cm column at approximately 40 psi, eluting with 0.5% acetone in methylene chloride and collecting 200 ml fractions. Fraction 3 contains 1.5 g of tan solid, m.p. 99.0°-105.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][C:4]([C:13]#[N:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(Cl)cc(C#N)nc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
To a solution of 4-chloro-7-methylquinoline-2-carbonitrile (6.66 g, 33 mmol) in CCl4 (160 mL) was added NBS (6.46 g, 36.3 mmol) and benzoyl peroxide (800 mg, 3.3 mmol). The mixture was heated under reflux overnight, cooled to room temperature and evaporated to dryness. The reaction mixture was purified by flash chromatography on silica gel (eluting solvent: dichloromethane/hexane, 9/1) to provide the title compound (8.46 g). 1HNMR (400 MHz, acetone-d6): δ 8.37 (d, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.05 (d, 1H), 4.95 (s, 2H).
Reaction SMILES: [CH2:1](OS(OCC)(=O)=O)[CH3:2].[C:10]([C:18]1[C:19]([N:30]([CH2:41][CH3:42])S(C2C=CC(C)=CC=2)(=O)=O)=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:21][C:22]=1[CH3:23])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([C:18]1[C:19]([NH:30][CH2:41][CH3:42])=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:21]([CH2:1][CH3:2])[C:22]=1[CH3:23])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(c1c(-c2ccccc2)[nH]c(C)c1C(=O)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOS(=O)(=O)OCC
Product: CCNc1c(C(=O)c2ccccc2)c(C)n(CC)c1-c1ccccc1

Procedure:
Compound B) is transformed into the corresponding p-toluene sulfonamido derivative (M.p. 230°-33° C) by reaction with p-toluenesulfonychloride. This compound is subsequently reacted in strong alkaline solution with diethylsulfate, thus obtaining 4-benzoyl-3-(N-ethyl-p-toluenesulfonamido)-5-methyl-2-phenyl-pyrrole (M.p. 152°-53° C), which is in turn converted into the title compound (B.p. 220° C/0.015 mmHg) by acid hydrolysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:24]>C1COCC1.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:24])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 4.565 g (20 mmol) 4-benzyloxybenzoic acid in 25 ml THF and 0.3 ml N,N-dimethylformamide was added dropwise at 0° C. a solution of 2.6 ml oxalyl chloride in 5 ml THF. Stirring was continued for 3 hours at room temperature, then the suspension was added slowly to a stirred ice-cold solution of concentrated aqueous ammonia. The organic solvent was evaporated, 100 ml water added and the precipitate isolated and dried in vacuo at 50° C. Yield: 4.29 g (94%) white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19](OC)(OC)OC>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([CH3:10])([CH3:11])[O:12][C:17]([O:18][CH3:19])=[N:16][S:13]2(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(C)(O)C(c1cccc(Br)c1)S(N)(=O)=O
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2cccc(Br)c2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 500 mg of 1-(3-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide in 2 ml of tetramethoxymethane and 0.5 ml of acetic acid was stirred at 100° C. for 3 hours. After the removal of the solvent under reduced pressure, the residue (565 mg) was used in the next reaction without further purification.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:39][CH:40]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[N:39][CH:40]=4)=[N:3][CH:4]=[CH:5][CH:6]=3)[N:9]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
4-(2-Fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.150 g, 0.337 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.0841 g, 0.402 mmol) were dissolved in THF (3 mL). The mixture was cooled to 0° C. and LiHMDS (Acros) (1.4 mL, 1.4 mmol) was added slowly. The dark red mixture was stirred at 0° C. for 1 h. The reaction mixture was partitioned between saturated aqueous ammonium chloride (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25 g, eluent: EtOAc in hexanes 0%-50%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.145 g, 68% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.83 (s, 1H); 8.76-8.87 (m, 1H); 8.39-8.48 (m, 1H); 8.25-8.34 (m, 1H); 7.91-8.03 (m, 1H); 7.76-7.87 (m, 1H); 7.10-7.24 (m, 5H); 6.86 (t, J=7.09 Hz, 4H); 6.70-6.81 (m, 1H); 4.83 (br. s., 4H); 3.80 (d, J=5.70 Hz, 6H); 2.58 (s, 3H); 1.53 (s, 9H). m/z (ESI, +ve ion) 635.0 (M+H)+.
Reaction SMILES: [Si]([O:18][C@@H:19]([CH3:46])[C:20]([N:22]1[N:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[S:24][C@:23]1([CH2:41][O:42][CH2:43][O:44][CH3:45])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F[C:48]1C=CC(F)=CC=1C1S[C@@](CO)(C2C=CC=CC=2)N(C(=O)[C@@H](OC)C)N=1>>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:25]1[S:24][C@:23]([CH2:41][O:42][CH2:43][O:44][CH3:45])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:22]([C:20](=[O:21])[C@@H:19]([O:18][CH3:48])[CH3:46])[N:26]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CO)c1ccccc1
Reactant: COCOC[C@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: COCOC[C@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC

Procedure:
Prepared as previously described in Example 83 using (S)-2-(tert-butyldiphenylsilyloxy)-1-((S)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one from Step C. MS ESI (+) m/z 437 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.53 (m, 1H), 7.43 (m, 2H), 7.37 (m, 2H), 7.31 (m, 1H), 7.11 (m, 2H), 4.76 (m, 4H), 4.47 (d, 1H, J=10 Hz), 3.41 (s, 3H), 3.35 (s, 3H), 1.47 (d, 3H, J=7 Hz). Stereochemistry was assigned by inference from (S)-1-((R)-5-(2,5-difluorophenyl)-2-(hydroxymethyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].C(O)(=O)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[Cl:13][C:6]1[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]2[NH:1][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:4][C:3]=2[CH:5]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: NS(=O)(=O)c1cc2[nH]c(-c3ccccc3)nc2cc1Cl

Procedure:
A mixture of 2.21 g. of 2-amino-4-chloro-5-sulfamylaniline (VI), 50 ml. of glacial acetic acid, and 1.05 g. of benzaldehyde was refluxed for 16 hours and then decanted into water. The precipitate was collected by filtration, dissolved in ethanol, treated with Darco, filtered through filter paper and then through Celite. Concentration in vacuo provided a solid which was dissolved in ethanol, filtered, and forced out with water. Treatment of this beige solid with boiling acetronitrile provided an off-white solid mp 314°-316°.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2([CH3:23])[O:16][C:15]3=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]3[CH2:13]2)[C:7]1=[O:24].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:23][C:12]1([CH2:11][N:8]2[CH2:9][CH2:10][NH:6][C:7]2=[O:24])[O:16][C:15]2=[N:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][N:14]2[CH2:13]1
Reactant: COc1ccc(CN2CCN(CC3(C)Cn4cc([N+](=O)[O-])nc4O3)C2=O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2CCNC2=O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 1-(2,4-dimethoxybenzyl)-3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)imidazolidin-2-one prepared in Example 594 (100 mg, 0.24 mmol), trifluoroacetic acid (2 ml) and methylene chloride (2 ml) was stirred at room temperature for 1 hour. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added for neutralization. The resulting solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was treated with diethyl ether to afford 1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)imidazolidin-2-one (50 mg, yield 78%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]1[CH:26]([CH2:27][C:28]([OH:30])=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)(=[O:12])=[O:11].Cl.Cl.[NH:33]1[CH2:37][CH2:36][N:35]=[C:34]1[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][NH2:46])=[CH:40][CH:39]=1>>[NH:35]1[CH2:36][CH2:37][N:33]=[C:34]1[C:38]1[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][NH:46][C:28](=[O:30])[CH2:27][CH:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]2[S:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])(=[O:11])=[O:12])=[CH:42][CH:43]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)O)c(C)c1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Product: Cc1cc(C)c(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)NCCc2ccc(C3=NCCN3)cc2)c(C)c1

Procedure:
The title compound was prepared from [5-(2,4,6-trimethyl-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e.