Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]#[N:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:36][OH:37]>C(O)C>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](=[NH:27])[NH:36][OH:37])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: NO
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(C#N)cccc4c3nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(C(=N)NO)cccc4c3nc12
Yield: 91.8 %

Procedure:
A mixture of 4-cyano-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (20 mg), potassium carbonate (37 mg) and hydroxylamine hydrochloride (19 mg) was heated to reflux in ethanol (5 mL) for 18 hours. The reaction mixture was filtered, and the filtrate was collected and the solvent removed in vacuo to yield the title compound (20 mg).
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25]([N:1]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]2[C:3]([O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:4])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)N2CCCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (14) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylamine. The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (elution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (8) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (br d) 4.03 (br d), 3.83 (s), 3.37 (dt), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43 (m), Rf 0.40 (1:1 ether-hexane).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:13][C:2]([F:12])([F:1])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccc(SC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(SC(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A mixture of 4-(trifluromethylthio)benzylamine (250 mg, 1.21 mmol), benzoyl chloride (178 mg, 1.27 mmol) and sodium bicarbonate (508 mg, 6.05 mmol) in DCM (15 mL) was stirred at rt until the reaction completed. The reaction was diluted with ethyl acetate, washed with brine and dried to give 372 mg (99%) of N-(4-trifluoromethylthiobenzyl)benzamide as a white solid. 1HNMR (360 MHz, DMSO-d6) δ 9.07 (m, 1H, NH), 7.88-7.90 (m, 2H), 7.66-7.68 (d, J=8.7 Hz, 2H), 7.45-7.56 (m, 5H), 4.53 (d, J=6.1 Hz, NCH2, 2H). MS-EI m/z 311 [M+].
Reaction SMILES: Cl.[CH2:2]([C:9]1[O:13][N:12]=[C:11]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:20][C:21]1[CH:33]=[CH:32][C:24]2[NH:25][C:26]([S:28](Cl)(=[O:30])=[O:29])=[N:27][C:23]=2[CH:22]=1>>[CH2:2]([C:9]1[O:13][N:12]=[C:11]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[S:28]([C:26]2[NH:25][C:24]3[CH:32]=[CH:33][C:21]([Br:20])=[CH:22][C:23]=3[N:27]=2)(=[O:30])=[O:29])[N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(Cc2nc([C@@H]3CCCCN3)no2)cc1
Reactant: O=S(=O)(Cl)c1nc2cc(Br)ccc2[nH]1
Agent: Cl
Product: O=S(=O)(c1nc2cc(Br)ccc2[nH]1)N1CCCC[C@H]1c1noc(Cc2ccccc2)n1

Procedure:
The title compound was prepared by a similar method to Example 1 from 5-benzyl-3-[(2S)-2-piperidyl]-1,2,4-oxadiazole hydrochloride [see-Preparation 7] and 5-bromo-1H-benzo[d]imidazole-2-sulfonyl chloride [see Preparation 88]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by volume, hexane:ethyl acetate, in 10% increments, to afford 2-[(2S)-2-(5-benzyl-1,2,4-oxadiazol-3-yl)-1-piperidyl]sulfonyl-5-bromo-1H-benzo[d]imidazole as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: C1CCNC1
Product: O=S(=O)(c1ccc(I)cc1)N1CCCC1

Procedure:
The title compound was prepared from 4-iodobenzenesulfonyl chloride and pyrrolidine using a similar procedure to that described for Description 30.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:18][C:19]1[C:24]2[B:25]([OH:28])[O:26][CH2:27][C:23]=2[CH:22]=[C:21]([OH:29])[CH:20]=1>>[Cl:1][C:2]1[C:3]([O:29][C:21]2[CH:20]=[C:19]([CH3:18])[C:24]3[B:25]([OH:28])[O:26][CH2:27][C:23]=3[CH:22]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(=O)CCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: Cc1cc(O)cc2c1B(O)OC2
Product: CC(=O)CCCOc1nc(Oc2cc(C)c3c(c2)COB3O)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(4-oxopentyloxy)nicotinonitrile and 7-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.67-1.71 (m, 2H), 2.02 (s, 3H), 2.33 (t, J=5.4 Hz, 2H), 2.44 (s, 3H), 4.01 (t, J=5.3 Hz, 2H), 4.95 (s, 2H), 7.0 (s, 1H), 7.07 (s, 1H), 8.56 (s, 1H), 9.0 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][NH:21][C:22](=O)[O:23]C1C=CC=CC=1.O>CN(C)C=O>[CH3:20][NH:21][C:22]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:23]
Reactant: CNC(=O)Oc1ccccc1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Sodium hydride (2.212 g, 55.30 mmol, 60% in oil) was suspended in N,N-dimethylformamide (100 ml), 5-benzyloxyindole (10.29 g, 46.09 mmol) was added thereto while stirred at room temperature, and the reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was cooled with an ice water bath, and phenyl N-methylcarbamate (8.360 g, 55.30 mmol) was added. After the reaction mixture was stirred for 30 minutes, the solution was stirred at room temperature for 2.5 hours. After water was added to the reaction mixture and the reaction mixture was stirred at room temperature for 1 hour, the crystals were sequentially washed with water and diethyl ether, and dried under aeration to yield the title compound (12.07 g, 43.06 mmol, 93.41%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C>>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:16]1([C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:22])[O:21]1
Reactant: CCn1c2ccccc2c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CCn1c2ccccc2c2cc(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)ccc21

Procedure:
A mixture of 3.43 g (0.01 mole) of 2-[(9-ethyl-3-carbazolyl)carbonyl]benzoic acid, 1.80 g (0.011 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 4.0 ml of acetic anhydride was interacted in a manner similar to that described in Example 1, part C above to yield 3-[2,4-bis(dimethylamino)phenyl]-3-(9-ethyl-3-carbazolyl)phthalide (Formula V: R°=R1 =R2 =R3 =H; R=CH3 ; R4 =N(CH3)2 ; R8 =CH2CH3) which melted over the range 134°-142° C. A significant infrared absorption maximum appeared at 1753 cm-1 (C=O; s). A toluene solution of this product spotted on silica gel developed a bordeaux-colored image.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3]1.[CH2:15]([NH2:18])[CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=[N:18][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:6]2)[O:4][CH2:3]1
Reactant: CCCN
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCN=C1CCC2(CC1)OCC(C)(C)CO2

Procedure:
A 500 ml round bottom flask was charged with 20.32 g (0.103 mol) of 3,3-dimethyl-1,5-dioxazpiro[5.5]undecan-9-one (also known as 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal, from Aldrich Chemical Company, Milwaukee, Wis.), 21.6 g (0.365 mol) of n-propylamine (Eastman Chemical Company, Rochester, N.Y.), 0.01 g of p-toluenesulfonic acid and 100 ml of toluene. The reaction mixture was refluxed for 24 hours with a water separator charged with 16 g of 3-A molecular sieves. The volatiles were removed in vacuo and the residue was held for further synthetic modifications as described below.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[S-:13][C:14]#[N:15].[K+].BrBr>C(O)(=O)C>[NH2:15][C:14]1[S:13][C:12]2[CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.9 %

Procedure:
A solution of ethyl 4-aminobenzoate (8.26 g, 0.05 mol) in acetic acid (100 mL) was treated with potassium thiocyanate (14.58 g, 0.15 mol) and stirred 10 minutes at room temperature to dissolve the salt. The resulting solution was cooled in an ice bath and stirred while bromine (2.6 mL, 0.05 mol) was added dropwise over 15 minutes. The cooling bath was removed and the mixture was stirred at room temperature for 2.25 hours. The mixture was stored at 5° C. for 5 hours, then filtered to remove the yellow precipitate. The filter cake was washed with diethyl ether (2×50 mL) and water (2×100 mL) and dried under vacuum to give 2-amino-6-ethoxycarbonylbenzothiazole (2.54 g) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1.O1CCCC1.[OH-].[K+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(-c2ccccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
700 mg (3.11 mol) of methyl [4-(2-pyridyl)phenyl]acetate are introduced into 5 ml of tetrahydrofuran and, at room temperature, 6.2 ml of a 1M potassium hydroxide solution in water are added. The mixture is stirred at room temperature for 18 h and then the solvent is substantially removed in vacuo, the residue is taken up in 10 ml of water and the pH was adjusted to about 5 with 2N hydrochloric acid. Extraction of the aqueous phase twice with 10 ml of dichloromethane each time affords, after drying the combined organic phases over magnesiumsulfate and removing the solvent in vacuo, the compound of Example VIII in the form of a solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:23]=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(O)c1ccccc1Nc1cccc(OCc2ccccc2)c1

Procedure:
2-(3-Benzyloxyphenylamino)benzoic acid [VII; R and R"=H, OR°=3--OCH2C6H5 ] was prepared from 2-chlorobenzoic acid and 3-benzyloxyaniline according to the procedure of Example 1(a). The green solid obtained was used directly in the next reaction.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:6]1)[CH3:4].Cl[C:22]1[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]=1.O>CN(C=O)C>[CH2:3]([N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:25]4[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=4[N:23]=3)=[CH:16][CH:15]=2)=[N:6]1)[CH3:4]
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CCn1nc(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
NaH (60% in oil, 59 mg) was added portionwise at room temperature to a solution of 4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (335 mg) in DMF (3.5 mL). After stirring for 30 min, 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (416 mg) was added, and the mixture was heated for 2 h at 150° C. under microwave irradiation. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give the title compound (530 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:36][CH3:37])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([NH:30][C:31](=[O:34])[CH2:32][Br:33])=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:35])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].C(Cl)Cl>>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Br:33][CH2:32][C:31]([NH:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:35])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8](=[NH:7])[NH2:9])[S:11][C:12]=2[S:36][CH3:37])(=[O:17])=[O:16])[CH:19]=1)=[O:34]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CBr)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CBr)c1
Yield: 68 %

Procedure:
({4-[6′-(2-bromo-acetylamino)-2′-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (22 mg, 0.034 mmol, as prepared in Example 246, step a) was stirred in a mixture of TFA/DCM (1:1, 4 mL) for 1 h at rt. The reaction was concentrated in vacuo and the resulting residue was purified using RP-HPLC (10–50% CH3CN in H2O with 0.1% TFA over 30 min) to afford 15 mg (68%) of the title compound as a clear glassy solid (purity>99.9% by analytical RP-HPLC). ESI-MS (m/z): Calcd. for C21H20BrN3O3S3: 538.0 (M+H); found: 538.0 and 540.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([F:22])[F:21])=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:23]=1.C[O-].[Na+].C([NH2:29])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:20]([F:21])[F:22])=[C:14]([C:16]([NH2:29])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:23]=1
Reactant: COC(=O)c1nc2n(c1C(F)F)C1CC(C1)c1ccc(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)c1nc2n(c1C(F)F)C1CC(C1)c1ccc(Br)cc1-2
Yield: 100 %

Procedure:
10-bromo-3-(difluoromethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L Methyl 10-bromo-3-(difluoromethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 70.2 mg (100% yield) of the crude title compound which was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH2:15])[CH:11]=[CH:12]2)=[N:7]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:15][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:26][CH:27]=3)=[O:33])[CH:11]=[CH:12]2)=[N:7]1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: COC(CCn1cc2ccc(N)cc2n1)OC
Solvent: C1CCOC1
Product: COC(CCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1)OC

Procedure:
To a stirred solution of 2-(3,3-dimethoxypropyl)-2H-indazole-6-ylamine (582 mg, 2.48 mmol) in THF (9 mL) was added 4-phenoxyphenylisocyanate (523 mg, 2.48 mmol) and the reaction was heated to 40 C for 3 h. The heating bath was removed and the reaction was then concentrated under reduced pressure to a dark oil. The oil was dissolved in Ethyl acetate and passed through a small plug of SiO2 gel, eluting with additional EtOAc. The eluent was concentrated under reduced pressure to give 1-[2-(3,3-dimethoxypropyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea as a beige solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.50 (m, 2 H), 3.32 (m, 6 H), 4.36 (m, 3 H), 6.97 (m, 6 H), 7.09 (t, J=7.46 Hz, 1 H), 7.36 (m, 2 H), 7.48 (m, 2 H), 7.59 (d, J=8.82 Hz, 1 H), 7.83 (s, 1 H) and 8.66 (m, 2 H); MS(ESI) 445 (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH3:8][N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=[N:10]1.Br[C:24]1[CH:25]=[C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=[CH:28][C:29]=1[F:30]>C(#N)C>[F:30][C:29]1[CH:24]=[CH:25][C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][C:28]=1[C:12]1[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=1
Reactant: COC(=O)Cc1ccc(F)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1ccc(F)c(-c2cnn(C)c2)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Pd-118 (0.201 g) was dissolved in acetonitrile (20 mL) and stirred for 5 min before addition of potassium carbonate (5.34 g), water (20 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.95 g). The mixture was stirred for a further 5 min then methyl 2-(3-bromo-4-fluorophenyl)acetate [Example 13, Step i)] (3.18 g) in MeCN (2 mL) added and the reaction was heated at the heating block (80° C.) for 25 min. The mixture was cooled and extracted into DCM (100 mL). Organic was separated, dried over magnesium sulfate. Solvents were evaporated to give a brown oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in isohexane to afford the subtitled compound (3.36 g) as a gum. 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.44 (dd, J=7.3, 1.5 Hz, 1H), 7.12-7.02 (m, 2H), 3.96 (s, 3H), 3.71 (s, 3H), 3.62 (s, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10]C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:28][CH:29]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(CO)CBr
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC(C)(C)CO)cc2)c2ccccc21
Temperature: 95 °C

Procedure:
(±)-Cis-N-(4-chloro-phenyl)-N-{1-[4-(3-hydroxy-2,2-dimethyl-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide (210 mg, 0.484 mmol) was dissolved in DMF (10 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propan-1-ol (813 mg, 4.84 mmol), the reaction was heated to 95° C. and stirred over night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate-70/30 dichloromethane/ethyl acetate) to afford the pure ester (110 mg, 44%)
Reaction SMILES: [OH:1][C@@H:2]([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([CH2:16][O:15][C:14]3[CH:17]=[C:18]4[C:22](=[CH:23][C:13]2=3)[CH2:21][CH2:20][O:19]4)[C:5]1=[O:24].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:28]([O:1][C@@H:2]([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([CH2:16][O:15][C:14]3[CH:17]=[C:18]4[C:22](=[CH:23][C:13]2=3)[CH2:21][CH2:20][O:19]4)[C:5]1=[O:24])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a stirred solution of 1′-[(2S)-2-hydroxypropyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.19 mg, 0.56 mmol) in anhydrous tetrahydrofuran (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.03 g, 0.71 mmol). The solution was stirred at ambient temperature for 30 min, then benzylbromide (0.14 g, 0.84 mmol) was added. The reaction mixture was stirred for 16 h. The solution was cooled to ambient temperature, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (25%) to afford 1′-[(2S)-2-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.20 g, 77%) as a colorless solid: mp 45-47° C.; 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.30-6.97 (m, 9H), 6.38 (s, 1H), 6.33 (d, J=36.0 Hz, 1H), 4.84 (dd, J=21.7, 8.9 Hz, 1H), 4.68-4.55 (m, 2H), 4.49 (dt, J=8.6, 0.8 Hz, 2H), 4.40 (dd, J=12.0, 3.8 Hz, 1H), 4.01-3.83 (m, 2H), 3.80-3.68 (m, 1H), 2.88 (t, J=8.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.1 (2), 161.7 (2), 161.3 (2), 143.0 (2), 138.3 (2), 132.7, 128.6, 128.3 (2), 127.5 (2), 127.3, 123.6 (2), 123.2, 120.3 (2), 119.8 (2), 118.9 (2), 109.7 (2), 93.2, 80.7 (2), 73.2, 72.8, 72.4, 70.9, 70.7, 57.6, 46.1 (2), 29.0 (2), 17.7 (2); MS (ES+) m/z 428.0 (M+23).