Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].S([O-])([O-])(=O)=[O:37].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][S:13]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][C:21](=[O:37])[C:20]=3[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3)CC1
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
4-[4-(2-Methyl-benzoylamino)-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid ethyl ester (1.12 g, 2.24 mmol) was dissolved in acetone (25 mL) and a 15% aqueous solution of magnesium sulfate(2.5 mL). The solution was cooled in an ice bath and potassium permanganate (1.9 g, 12.3 mmol) was added and the solution was stirred for 15 min at which time the solution was allowed to warm to room temperature and stirred for 3 hr. The solution was concentrated and diluted with 150 mL water. The product was exhaustively extracted from the aqueous layer with methylene chloride. The organic was then washed with brine, dried over anhydrous magnesium sulfate, concentrated and purified on silica (Isco flash column, 0 to 40% ethyl acetate in hexane). The title compound was isolated in 17% yield (200 mg).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:8]=1[F:16])(=O)=O.[N-:17]=[N+:18]=[N-].[Na+].C[N:22](C=O)C>O>[N:15]([CH2:14][C:10]1[CH:11]=[C:12]([F:13])[C:7]([C:6]#[N:22])=[C:8]([F:16])[CH:9]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1c(F)cc(C#N)cc1F
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: N#Cc1c(F)cc(CN=[N+]=[N-])cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-2,6-difluorobenzyl methanesulfonate (1.61 g, 6.51 mmol; see step (iv) above) and sodium azide (0.72 g, 0.0111 mol) in 10 mL of water and 20 mL of DMF was stirred at room temperature overnight. The resultant was subsequently poured into 200 mL of water and extracted three times with diethyl ether. The combined ethereal phase was washed five times with water, dried (Na2SO4) and evaporated. A small sample was evaporated for NMR purposes and the product crystallised. The rest was evaporated cautiously but not until complete dryness. Yield (theoretically 1.26 g) was assumed to be almost quantitative based on NMR and analytical HPLC.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@@H](CO)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a solution of 12.18 g (0.0756 mol) of L-serine, t-butyl ester, 26.52 ml of triethylamine in 160 ml of CH2Cl2 (cooled in an ice bath) was added, in small portions, 16.1 g (0.0771 mol) of 4-methoxybenzene-sulfonyl chloride. The mixture was stirred at 0° C. for 0.5 hours and at room temperature overnight. The mixture was washed with H2O, 2N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 25.34 g of solid which was triturated with hexane. The solid was recrystallized from 120 ml of toluene to give 12.18 g (48.7%) of product as a white solid. The filtrate was concentrated and the residue chromatographed on silica gel with hexane-ethyl acetate (7:3) as eluent to give 5.71 g (22.8%) of white solid. m.p. 70-75° C. Anal. for C14H21NO6S: Calc'd: C. 50.7; H,6.4; N,4.2; Found: C, 50.4; H,6.3; N,4.4.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([C:18]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: O=C(Cl)C1CCCC1
Solvent: CCO
Solvent: O
Product: O=C(C1CCCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperazine hexahydrate (8.55 g, 44.0 mmol) was dissolved in absolute ethanol (50 ml) and then refluxed for 10 min. Cyclopentanecarbonyl chloride (5.83 g, 44 mmol) was added dropwise at 65° C. and the reaction mixture was refluxed for 30 min and then stirred at room temperature for 18 h. The reaction mixture was cooled, filtered and the filtrate was concentrated in vacuo to give ˜20 ml of solution. The concentrate was cooled and then filtered again. Ethanolic hydrogen chloride was added to the mother liquor, and the reaction mixture was concentrated to give a white solid, which was dissolved in water (15 ml). The solution was basified to pH 14 and the product was extracted with dichloromethane (7×50 ml). The extracts were dried, (Na2SO4) and concentrated to give the title compound as a yellowish residue, which was distilled to give the product (1.28 g, 7.0 mmol, 16%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (Aldrich, 3.0 g, 17.2 mmol) in sulfuric acid (18 mL) was added nitric acid (60-61%, Wako Pure Chemical Industries, Ltd., 6 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was poured into ice water and obtained precipitate was collected by filtration. The solid was washed with water and dried in vacuo to afford the title compound (2.5 g, 68%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[H-].[Na+].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([O-:13])=[O:12].O>CN(C)C=O.O1CCCC1>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[C:3]1=[O:4]
Reactant: CN1CC(=O)NC1=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CN1CC(=O)N(Cc2ccc([N+](=O)[O-])cc2)C1=O
Reaction time: 0.5 h

Procedure:
To a mixture solution of 685 mg (6.0 mmol) of 1-methylhydantoin in 10 mL of N,N-dimethylformamide and 10 mL of tetrahydrofuran was added 240 mg (6.9 mmol) of sodium hydride (60% oily) at room temperature, and the mixture was stirred for 30 minutes at the same temperature. Then, 1.08 g (5.0 mmol) of p-nitrobenzyl bromide was added to the reaction mixture, and the mixture was stirred for over night at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 1.38 g (quantitative) of the title compound.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:8]=1.[N+](C1C=CC([O:29][C:30]([O:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:42]=2)[C:38]([O:40][CH3:41])=[O:39])=O)=CC=1)([O-])=O>C(#N)C>[Br:2][CH2:3][CH2:4][NH:5][C:6]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:30]([O:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([CH:42]=3)[C:38]([O:40][CH3:41])=[O:39])=[O:29])[CH2:17][CH2:16]2)[CH:10]=[CH:11][CH:12]=1)=[O:21]
Reactant: O=C(NCCBr)c1cccc(CCC2CCNCC2)c1
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Solvent: CC#N
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C(=O)NCCBr)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
TEA (0.90 ml) was dropwise added to an acetonitrile (30 ml) suspension of N-(2-bromoethyl)-3-(2-piperidin-4-ylethyl)benzamide hydrochloride (1.20 g) and methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (1.02 g), followed by stirring overnight at room temperature. The reaction solvent was evaporated under reduced pressure, then aqueous saturated sodium hydrogencarbonate solution was added thereto, extracted with EtOAc, and dried over anhydrous magnesium sulfate. This was filtered, the solvent was evaporated, and the residue was purified two times through silica gel column chromatography (basic silica with eluent: hexane:EtOAc=1:2 (v/v), next neutral silica with eluent: chloroform:methanol=19:1 (v/v)) to obtain methyl 5-[{(4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidin-1-yl}carbonyl)oxy]nicotinate (762 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:36]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.C(N(CC)CC)C>[CH2:36]([N:43]1[CH2:48][CH2:47][CH:46]([NH:49][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:13])[CH2:45][CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a stirred mixture of 5-hydroxy-1H-indole-2-carboxylic acid (1.85 g, 10.43 mmol) in anhydrous dimethylformamide (15 mL) was added triethylamine (1.73 mL), 1-hydroxybenzotriazole (1.64 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.39 g) and 1-benzylpiperidin-4-ylamine (2.39 g, 12.54 mmol). The reaction mixture was stirred at room temperature over-night and then solvents were removed under reduced pressure, poured into water, filter the solid and washed with water. The solid was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH (93:7) to afford 0.87 g (24%) of N-(1-benzylpiperidin-4-yl)-5-hydroxy-1H-indole-2-carboxamide as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 11.17 (s, 1H), 8.72 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.7.29 (m, 6H), 6.91 (s, 1H), 6.82 (s, 1H), 6.68 (m, 1H), 3.75 (br s, 1H), 3.46 (s, 2H), 2.81 (d, J=11.4 Hz, 2H), 2.02 (t, J =10.8 Hz, 2H), 1.77 (m, 2H), 1.56 (m, 2H); LCMS (m/z): 350 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[C:9](F)=[CH:8][C:7]=1[Cl:14])[C:2]#[CH:3].[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].Cl>CN(C=O)C>[CH2:1]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:19][CH2:16][C:17]#[CH:18])=[CH:8][C:7]=1[Cl:14])[C:2]#[CH:3]
Reactant: C#CCOC(=O)c1cc(F)c(F)cc1Cl
Reactant: C#CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(=O)c1cc(F)c(OCC#C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.4 %

Procedure:
To a mixed solution of 150 ml of DMF, 12.7 g of 2-chloro-4,5-difluorobenzoic acid 2-propynyl ester and 3.4 g of propargyl alcohol, 2.4 g of 60% sodium hydride (oily) was added under ice cooling. After stirring at room temperature overnight, the reaction mixture was added with hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed in turn with water and saturated brine, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 19 g of 2-chloro-5-fluoro-4-(2-propynyloxy)benzoic acid 2-propynyl ester was obtained.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)[CH3:19])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][CH:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)[CH3:19])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]3[N:37]=[CH:38][CH:39]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-{1-[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile (0.37 g) in tetrahydrofuran (4 mL) was added 3M hydrochloric acid (4 mL), and the mixture was stirred at 60° C. for 3 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 1 M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (3 mL)-tetrahydrofuran (3 mL). Thereto was added sodium borohydride (0.026 g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.33 g, 99%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:25]([CH3:26])=[CH:24][C:18]2[N:19]([CH3:23])[C:20](=[O:22])[S:21][C:17]=2[C:16]=1[Br:27])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(OC[C@H](C1C(C)=CC2N=C(O)SC=2C=1Br)OC(C)(C)C)(=O)C(C)(C)C.[CH3:54][Si:55]([CH3:62])([CH3:61])[CH2:56][CH2:57][O:58]CCl>>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:25]([CH3:26])=[CH:24][C:18]2[N:19]([CH2:23][O:58][CH2:57][CH2:56][Si:55]([CH3:62])([CH3:61])[CH3:54])[C:20](=[O:22])[S:21][C:17]=2[C:16]=1[Br:27])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: Cc1cc2c(sc(=O)n2C)c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: Cc1cc2nc(O)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2c(sc(=O)n2COCC[Si](C)(C)C)c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
Prepared by the similar method to make (S)-2-(7-bromo-3,5-dimethyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67C) in example 26 from 67B using 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) instead of methyl iodide.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:12]1([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([NH2:28])[C:25]([NH2:27])=[O:26])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.CCN(C(C)C)C(C)C>CS(C)=O>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C@@H:24]([NH:28][C:8]3[CH:9]=[C:2]([Br:1])[C:3]([C:4]#[N:5])=[CH:6][C:7]=3[F:11])[C:25]([NH2:27])=[O:26])=[CH:21][CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NC(=O)[C@H](N)Cc1ccc(-n2ccnc2)cc1
Reactant: N#Cc1cc(F)c(F)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(N[C@H](Cc2ccc(-n3ccnc3)cc2)C(N)=O)cc1Br
Yield: 31.7 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (100 mg, 0.458 mmol), ((R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-aminopropanamide (100 mg, 0.434 mmol) and DIEA (0.100 mL, 0.575 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. The mixture was purified by HPLC to give (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(5-bromo-4-cyano-2-fluorophenylamino)propanamide (59 mg).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](C(Cl)=O)=[CH:3][CH:2]=1.[C:11]([C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]2[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([NH:28][C:23]2[C:22]([NH:21][C:19](=[O:20])[C:18]3[CH:29]=[CH:30][C:15]([C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:16][CH:17]=3)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: Cc1ccc(Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 108 %

Procedure:
Using the procedure described in Example 93, Part A, 4-toluoyl chloride (1.1 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (0.93 mmol) yielded 360 mg (100%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClC(Cl)C.C(N(CC)CC)C>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)OCCCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To an iced-cooled solution of 4,4-diphenyl-1-butanol (5.6 g) in dichloroethane (100 mL), 11 mL of triethylamine and 2.9 mL of methanesulfonyl chloride were added dropwise in the order mentioned. After 30 minutes of stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated to provide 7.5 g of the title compound. Yield 99%.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)N.[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:14])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
5.0 g of 3-pentafluorosulfanylaniline were suspended in 50 ml of a 35% aqueous H2SO4 solution. Then, at 0° C., a solution of 1.57 g of NaNO2 in 5 ml of water was added dropwise over the course of 10 minutes. The mixture was stirred at 0° C. for 40 minutes. Then a solution, cooled to 0° C., of 8.56 g of Cu(NO3)2 in 50 ml of water was added to this suspension. Immediately thereafter, 3.26 g of Cu2O was also added, whereupon marked evolution of gas was observable. 3 extractions each with 100 ml of CH2Cl2 were carried out, the org. phase washed with 100 ml of a saturated aqueous NaCl solution and dried over MgSO4, and the solvent was removed in vacuo. Chromatography with DIP on a short silica gel column afforded 3.5 g of the phenol as colorless oil.
Reaction SMILES: [CH2:1](Br)[C:2]1C=CC=CC=1.ICC.[CH3:12][C:13]1[N:14]=[C:15]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:1]([N:25]1[CH2:26][CH2:27][N:23]([C:15]2[S:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:12])[N:14]=2)[C:24]1=[O:28])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Solvent: CCI
Product: CCOC(=O)c1sc(N2CCN(CC)C2=O)nc1C
Yield: 58 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with iodoethane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 58% yield: 1H NMR (300 MHZ, CDCl3) δ 4.29-4.04 (m, 4H), 3.64-3.33 (m, 4H), 2.63 (s, 3H), 1.38-1.05 (m, 6H); MS (ES+) m/z 284.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[H-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19]I>CN(C=O)C>[Cl:16][CH2:17][CH2:18][CH2:19][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:13]
Reactant: O=C1CCc2cc(F)c(F)cc2N1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A reaction flask was charged with 6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (97KK47) (0.181 g, 0.99 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.026 g, 1.08 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 3-chloro-1-iodopropane (0.205 g, 1.00 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et2O. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM) to give the title compound (112KK03) (0.122 g, 47%). 1H NMR (CD3OD) d 6.99-6.86 (m, 2H), 4.03-3.99 (m, 2H), 3.60 (t, J=6.1, CH2), 2.84-2.81 (m, 2H), 2.63-2.59 (m, 2H), 2.13-2.06 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])[C:9]2=O)=O)[N:3]=[CH:2]1.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH2:32]>N1C=CC=CC=1>[CH2:23]([O:30][N:31]=[C:6]([C:4]1[N:3]=[CH:2][O:1][CH:5]=1)[CH:8]1[CH2:9][N:10]([C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:11](=[O:32])[CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O
Reactant: C[C@@H](c1ccccc1)N1CCC(C(=O)c2cocn2)C1=O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@H](c1ccccc1)N1CC(C(=NOCc2ccccc2)c2cocn2)CC1=O
Temperature: 25 °C

Procedure:
4-(Oxazole-4-carbonyl-1-((S)-1-phenylethyl)pyrrolidin-2-one (0.5 g, 1.76 mmol) [Example 6B1] and O-benzylhydroxylamine, hydrochloride (0.42 g, 2.64 mmol) in pyridine (5 mL) were refluxed for five hours and then cooled to room temperature. The reaction mixture was diluted with water, washed with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with a mixture of 1:2 mixture of hexanes:ethyl acetate to provide 0.41 g of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.75-7.60 (m, 1H), 7.40-7.12 (m, 11H), 5.60-5.45 (m, 1H), 5.35-5.23 (m, 1H), 5.20-5.08 (m, 1H), 4.30-4.16 (m, 1H), 3.88-2.60 (m, 4H), 1.50-1.30 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([NH2:13])[NH:11][N:12]=1.[Na].[CH:15]([CH2:17][C:18](OCC)=O)=[O:16].Cl>C(O)C.O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[NH:13][CH:18]=[CH:17][C:15](=[O:16])[N:11]2[N:12]=1
Reactant: CCOC(=O)CC=O
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=c1cc[nH]c2cc(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine (I-1A-1a; 287 g, 1.48 mol) and ethyl formylacetate sodium salt (517 g, 3.74 mol) in ethanol (12 L) was heated at reflux for 6 hours. Additional ethyl formylacetate sodium salt (100 g, 0.72 mol) was added, and the reaction was heated at reflux for an additional 2 hours. After cooling to room temperature, the reaction was concentrated, in vacuo, to give an amber oil. The residue was redissolved in water (2 L) and then adjusted to pH 8 by dropwise addition of concentrated aqueous HCl. The solid precipitate that formed was isolated by vacuum filtration. This material was suspended in tetrahydrofuran (3 liters) and then stirred overnight. The solid was isolated by vacuum filtration and then dried, in vacuo, to afford I-1A-1b as an off-white solid (356 g, 98%): +APcI MS (M+1) 246.2; 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J=7.5 Hz, 1H), 7.85–7.82 (m, 1H), 7.58–7.53 (m, 1H), 7.46–7.41 (m, 2H), 6.58 (s, 1H), 5.71 (d, J=7.1 Hz, 1H).