Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36]>CN(C=O)C>[C:27]1(=[O:36])[N:26]([CH2:25][CH2:24][CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: CC1CC(=O)NN=C1c1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Yield: 104 %

Procedure:
A mixture of 500 mg (2.45 mmol) of 6-(4-hydroxyphenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (prepared by the method described in Eur. Pat. Appl. EP 178,189 A2), 373 mg (2.70 mmol) of powdered anhydrous K2CO3, and 790 mg (2.95 mmol) of N-(3-bromopropyl)phthalimide in 10 ml of DMF is heated at 100° C. for 2 hrs. The DMF is removed under vacuum, the residue is taken up in 125 ml of EtOAc and 100 ml of water, the organic phase washed once with 75 ml of water, dried (MgSO4), and the solvent removed to give 0.997 g of 6-[4-(3-phthalimidopropyloxy)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][C:14]([NH:16][CH3:17])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1.C(O)(C(F)(F)F)=O.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][CH2:14][NH:16][CH3:17])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: CNC(=O)CC(c1cccnc1)c1ccc2c(OC)n[nH]c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(c1cccnc1)c1ccc2c(OC)n[nH]c2c1

Procedure:
[3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-3-yl-propyl]-methyl-amine CCLI was prepared from 3-(3-methoxy-1H-indazol-6-yl)-N-methyl-3-pyridin-3yl-propionamide and TFA using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=298.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[N:4]([CH3:12])[CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:13][CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cn1cc(Br)c2ncnc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ncnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To 7-bromo-4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (200 mg) obtained in Step 4-4 of Preparation Example 4, t-butyl 4-hydroxypiperidine-1-carboxylate (180 mg), K2CO3 (168 mg) and N,N-dimethylformamide (4 ml) were added, and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[C:2]#[CH:3].Br[C:16]1[C:17]([NH:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:22]([C:19]1[N:20]=[CH:21][C:16]2[CH:3]=[C:2]([CH2:1][C:4]3[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[N:24]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=2[N:18]=1)#[N:23]
Reactant: C#CCc1ccc(CS(N)(=O)=O)cc1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Cn1c(Cc2ccc(CS(N)(=O)=O)cc2)cc2cnc(C#N)nc21
Temperature: 70 °C
Yield: 60.7 %

Procedure:
To a solution of N.-(4-prop-2-ynyl-phenyl)-methanesulfonamide (1.0 mmol) and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (0.5 mmol) in DMF (5 ml), triethylamine (1.5 mmol), dichlorobis-dichlorobis(triphenylphosphine)palladium (II) (0.05 mmol) and copper (I) iodide (0.1 mmol) is added. The reaction mixture is heated at 70° C. ca. for 2.5 h. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product, which is purified by silica gel column chromatography. Yield: 60.7%. Rf=0.55 (n-hexane:AcOEt=1:1)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:21]Br)=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:21]([C:19](=[O:20])[C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:9]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2cc3cc(Br)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.6 %

Procedure:
To 150 ml of acetone were suspended 20 g of 5-bromosalicylaldehyde, 22.9 g of 2-bromo-4-methoxyacetophenone and 27.6 g of anhydrous potassium carbonate. After stirring at room temperature for 4 hours, the resulting reaction solution was concentrated to dryness, and then mixed with water to collect precipitated crystals by filtration. After washing with water and subsequent recrystallization from ethanol, 14.02 g of 5-bromo-2-(4-methoxybenzoyl)benzofuran was obtained in the form of colorless prism crystals.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:30][CH:31]1[C:51](=[O:52])[N:33]2[C:34]([C:48]([OH:50])=[O:49])=[C:35]([CH2:38][S:39][C:40]3[N:44]([CH2:45][CH2:46][OH:47])[N:43]=[N:42][N:41]=3)[CH2:36][S:37][C@H:32]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:30][CH:31]2[C:51](=[O:52])[N:33]3[C:34]([C:48]([OH:50])=[O:49])=[C:35]([CH2:38][S:39][C:40]4[N:44]([CH2:45][CH2:46][OH:47])[N:43]=[N:42][N:41]=4)[CH2:36][S:37][C@H:32]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCO)CS[C@H]12
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCO)CS[C@H]12)c1csc(NC=O)n1
Yield: 69.2 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.), N,N-dimethylformamide (0.45 g.), phosphoryl chloride (1.0 g.), 7-amino-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (2 g.), trimethylsilylacetamide (5.9 g.) and ethyl acetate (50 ml.) were treated in a similar manner to that of Example 6-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.7 g.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:13][CH2:14][C:15](O)=[O:16])=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:18](=[O:23])[NH:19][CH:20]1[CH2:22][CH2:21]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[NH2:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CCCCCC.CN(C=O)C.C1COCC1>[CH:20]1([NH:19][C:18]([C:3]2[S:4][C:5]3=[N:6][C:7]([O:13][CH2:14][C:15](=[O:16])[NH:56][CH2:57][CH2:58][N:59]4[CH2:64][CH2:63][O:62][CH2:61][CH2:60]4)=[C:8]([Cl:12])[C:9]([CH3:11])=[C:10]3[C:2]=2[NH2:1])=[O:23])[CH2:21][CH2:22]1
Reactant: NCCN1CCOCC1
Reactant: Cc1c(Cl)c(OCC(=O)O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(Cl)c(OCC(=O)NCCN2CCOCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.4 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid (0.300 g, 0.843 mmol) in a 1:1 mixture of THF:DMF (2.0 ml each) are added 1-hydroxybenzotriazole hydrate (0.148 g, 1.096 mmol), N,N-diisopropylethylamine (0.163 g, 1.265 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.242 g, 1.265 mmol), and 4-(2-aminoethyl)morpholine (0.329 g, 2.529 mmol). The resulting solution is stirred at room temperature for 16 hours. The reaction is quenched by the addition of water (25 ml). If no precipitate forms, the mixture may be acidified to pH2 with 1 N HCl and extracted with EtOAc (25 ml). The organic layer is discarded and the aqueous layer is made basic (pH12) with 5N NaOH and extracted with EtOAc (40 ml). The organic layer is dried (anhydrous magnesium sulfate), filtered, and concentrated to give a yellow solid. The solid is slurried in 3:1 hexane:EtOAc (10 ml), then filtered. The collected solid is dried in the vacuum oven at 50° C. for 72 hours. This affords the title compound as a yellow solid (0.053 g, 13%). Mass (m/z): 468.2 (M++1), 466.2 (M+−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:15][CH:16]([CH3:34])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]>>[CH3:15][CH:16]([CH3:34])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:7](=[O:8])[C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:11]([F:14])([F:13])[F:12])[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (80%). m.p. 148-151° C. 1H NMR (400 MHz, CDCl3) δ 8.06, 7.85, 7.67, 7.54-7.50, 7.35, 7.01, 4.05-3.34, 1.73-1.46, 0.98. MS (ES+) m/z 484.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].Br[C:17]1[CH:18]=[C:19]2C(=[CH:25][CH:26]=1)C(=C(CC)CC)CCC2(C)C>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[C:17]([CH2:18][CH3:19])[CH2:26][CH3:25])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2]
Reactant: CCC(CC)=C1CCC(C)(C)c2cc(Br)ccc21
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=C(CC)CC

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 530 mg (1.66 mmol) of 6-bromo-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound Q) was converted into the title compound using 1.63 g (16.6 mmol) of trimethylsilylacetylene, 20 mg (0.08 mmol) of cuprous iodide, 60 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride and 40 mg (0.3 mmol) of potassium carbonate.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: ClCC1CO1
Product: c1cn(-c2ccc(OCC3CO3)cc2)cn1

Procedure:
The title compound was prepared from 4-imidazol-1-yl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: B#B.[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=2[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][CH2:6][C:5]1=O.Cl.N>O1CCCC1>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=2[C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:7][CH2:6][CH2:5]1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: B#B
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: CN1CCN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: -8 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a solution of 30 ml of 1.07 M diborane in tetrahydrofuran was added with stirring 1.48 g of 1-methyl-5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one at -13° to -8° C, and the mixture was further stirred at -8° C for 1 hour and 45 minutes. The reaction mixture was poured into ice-water, and 20 ml of concentrated hydrochloric acid was added. The mixture was refluxed for one hour. After cooling, the resultant solution was neutralized with 28%-aqueous ammonia, and extracted with chloroform. The chloroform extracts were washed with water and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in a 20%-solution of hydrochloric acid in ethyl alcohol, and refluxed for 10 minutes. The alcohol was removed by distillation under reduced pressure, and the residue was distributed between water and chloroform. The chloroform layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.34 g of 1-methyl-5-phenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepine, which was recrystallized from isopropyl alcohol to yield yellow flakes melting at 186° to 187° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][C:46]1=[O:51]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[C:46](=[O:51])[CH2:47]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: CN1CCNCC1=O
Agent: Cl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)N4CCN(C)C(=O)C4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylpiperazin-2-one hydrochloride.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[C:8](OCC)(=[O:11])[C:9]#[CH:10].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:2]([N:6]1[CH:10]=[CH:9][C:8]([OH:11])=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)NN
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)n1ccc(O)n1
Temperature: 35 °C
Reaction time: 8 h
Yield: 1.1 %

Procedure:
t-Butylhydrazine hydrochloride (4.5 g, 35.7 mmol) was suspended in t-butanol (35 ml) at room temperature in a dry nitrogen atmosphere. The mixture was warmed to 35° C., ethyl propiolate (3.85 g, 39.3 mmol) dropwise added and, after ice cooling, potassium t-butoxide (13.8 g, 107 mmol) was slowly added in small portions. The resulting mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo, water added to the residue and extracted with dichloromethane. The aqueous phase was acidified by addition of acetic acid, evaporated to dryness in vacuo and the residue was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and evaporated yielding 53 mg of 1-tert-butyl-1H-pyrazol-3-ol as a beige colour solid.
Reaction SMILES: C1CC(S)CC1.[CH:7]1([S:13]([C:16]2[CH:37]=[CH:36][C:19]([CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=4)[N:23]([CH2:31][C:32]([OH:34])=[O:33])[C:22]=3[CH3:35])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]C1>>[CH:7]1([S:13]([C:16]2[CH:37]=[CH:36][C:19]([CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=4)[N:23]([CH2:31][C:32]([OH:34])=[O:33])[C:22]=3[CH3:35])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Cc1c(Cc2ccc(S(=O)(=O)C3CCCCC3)cc2)c2cc(F)ccc2n1CC(=O)O
Agent: SC1CCCC1
Product: Cc1c(Cc2ccc(S(=O)(=O)C3CCCC3)cc2)c2cc(F)ccc2n1CC(=O)O

Procedure:
Cyclopentylthiol was used a starting material in Procedure A, otherwise this compound was prepared in a similar manner to Compound 6, using Procedures A, E, F, G, K & L.
Reaction SMILES: C1([C@H]([N:9]2[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:13]3[CH2:20][CH2:21][C@H:10]2[CH:11]=[CH:12]3)C)C=CC=CC=1>C(O)C>[CH:10]12[CH2:11][CH2:12][CH:13]([CH2:20][CH2:21]1)[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)[C@@H]1[C@H]2C=C[C@H](CC2)N1[C@H](C)c1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@H]1NC2CCC1CC2
Yield: 99.1 %

Procedure:
A solution of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (1.1 g) in ethanol (20 mL) was hydrogenated under H2 atmosphere (4 atm) for 2 hrs. After removal of the catalyst by filtration, the solvent was removed in vacuo to give the target compound as a colorless oil (700 mg).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)([O-:5])=[O:4].[CH3:15]I.O>CN(C=O)C>[CH3:15][N:10]1[C:11]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[N:9]1
Reactant: CI
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (1.1 g, 32.2 mmol; 60% dispersion in mineral oil) in DMF (40 mL) was treated with 4-nitro-1H-indazole (5 g, 30.6 mmol) in DMF (40 mL) at 0° C. After stirring for 30 minutes, the mixture was treated with methyl iodide (4.6 g, 32.18 mmol) in DMF (20 ml) drop wise. The mixture was allowed to gradually warm to ambient temperature and stir overnight. The mixture was poured into water (250 ml) and extracted with ethyl acetate (2×100 mL). The organics were combined, washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed (SiO2, ethyl acetate/hexanes) to provide the title compound. 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.24 (d, 1H), 8.19 (d, 1H), 7.65 (t, 1H).
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CC([Si](C)(C)[O:24][C:25]1[CH:26]=[C:27]([CH:31]([CH2:36][C:37]2[O:38][C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:41]=2)[C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1)(C)C.[NH4+].[Cl-]>C1COCC1>[OH:24][C:25]1[CH:26]=[C:27]([CH:31]([CH2:36][C:37]2[O:38][C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[C:40]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:41]=2)[C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A solution of nBu4NF (7.30 g, 28 mmol) in dry THF (27.9 mL) was added to a solution of methyl α-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-4,5-di phenyl-2-oxazolepropanoate (11.90 g, 23 mmol) in dry THF (250 mL) maintained at about -78° C. under an atmosphere of N2. After about 10 minutes, the mixture was poured onto saturated NH4Cl solution and extracted with CH2C2. The combined extracts were dried over Na2SO4, concentrated and the residue chromatographed on a column of silica gel. Elution with a mixture of Et2O and hexanes (1:1) gave methyl α- (3-hydroxyphenyl)-4,5-diphenyl-2-oxazolepropanoate (4.59 g, 47%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:35])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:9])[C:10]([NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:28]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:35]
Reactant: COc1ccc2occ(CC3CCCN3C(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2occ(CC3CCCN3C(=O)C(NC(=O)C(C)N)C(C)C)c2c1
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 33 (0.057 g, 0.11 mmol) in DCM (5 mL) was added TFA (1 mL) at ambient temperature. After 1 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (10% MeOH/DCM) to afford 0.015 g (35%) of 34 as a white solid. 1H NMR (CDCl3, 300 MHz) δ7.42 (m, 1H); 7.35 (d, 1H); 7.28 (m, 1H); 6.90 (dd, 1H); 4.60 (m, 1H); 4.48-4.45 (m, 1H); 3.89-3.76 (m, 4H); 3.65-3.56 (m, 2H); 3.31 (dd, 1H); 2.52-2.44 (m, 1H); 2.13-1.72 (m, 6H); 1.43-1.27 (m, 5H); 1.05-0.97 (m, 6H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18]CC3C=CC=CC=3)=[CH:15][CH:16]=2)[C:11]([OH:26])=[CH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(O)(=O)C.[C].[Pd]>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([OH:26])=[CH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(O)c2cc(OCc3ccccc3)ccc2n1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1cc(O)c2cc(O)ccc2n1Cc1ccccc1
Yield: 66.9 %

Procedure:
A solution of the title compound of Step (1) (2.8 g) in a mixture of methanol (180 ml) and acetic acid (75 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium-carbon (2.0 g) until no further uptake of hydrogen was observed. The reaction mixture was then filtered and the filtrate was evaporated to dryness. The solid residue was crystallized to give the title compound (1.4 g). That the expected product was obtained was confirmed by the spectral data: MS: m/e 267 (M.+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]([N:10]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[CH2:12][S:11]1(=[O:21])=[O:20])=[O:9])[CH3:6]>>[N+:1]([C:17]1[C:16]([F:19])=[CH:15][C:14]2[N:10]([C:8]([O:7][CH2:5][CH3:6])=[O:9])[S:11](=[O:21])(=[O:20])[CH2:12][C:13]=2[CH:18]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)N1c2cc(F)ccc2CS1(=O)=O
Product: CCOC(=O)N1c2cc(F)c([N+](=O)[O-])cc2CS1(=O)=O
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To stirred nitric acid (99%; 25 ml) was added 1-ethoxycarbonyl-1,3-dihydro-6-fluoro-2,1-benzisothiazole 2,2-dioxide (2.78 g) in portions at 0° C. The mixture was stirred for 2 hours while allowing it to warm to 10° C. The reaction mixture was poured into ice-water mixture then, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution. The extract was dried over magnesium sulfate and concentrated in vacuo. The resulting crude product was washed with methanol, to give 5-nitro-l-ethoxycarbonyl-1,3-dihydro-6-fluoro-2,1-benzisothiazole 2,2-dioxide (3.11 g).