Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[N-:30]=[N+:31]=[N-:32].[Na+]>CO.O>[N:30]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 3.0 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 50 ml of methanol is added a solution of 0.65 g of sodium azide in 5 ml of water under ice-cooling, followed by stirring for two hours at 40°-50° C. The solvent is distilled off under reduced pressure. To the residue is added ethyl acetate, and the organic layer is separated, which is washed with water and concentrated. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 1.01 g of (3S,4R)-4-azido-3-tritylamino-2-oxoazetidine.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]=[C:12]([NH2:13])[C:6]=2[CH:5]=1.[CH3:22][O:23][CH2:24][CH2:25][C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1>CS(C)=O.C1(C)C=CC=CC=1>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]=[C:12]([N:13]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:31]3)[C:6]=2[CH:5]=1
Reactant: NC1=Nc2ccccc2Nc2ccc(C(F)(F)F)cc21
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Yield: 61.8 %

Procedure:
Heat a suspension of 2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride salt (626 mg) and (S)-2-(2-methoxy-ethyl)-piperazine (863 mg) in DMSO (1.42 mL DMSO per mmol of amine) and toluene (5.68 mL per mmol of amine) at reflux for 48 hours. Evaporate the toluene under vaccuo and pour the resulting solution into water (5.71 mL per mmol of amine). Purify the resulting brown solid by flash chromatography (methylene chloride/methanol (95:5) to afford the title compound as a yellow solid (499 mg, 60%): mp 71-82° C.; 1HNMR (CDCl3) δ 1.75-1.60 (m, 2H), 2.64 (dd, 1H), 3.07-2.94 (m, 4H), 3.31 (s, 3H), 3.48 (ddd, 2H), 3.78 (bs, 2H), 5.09 (s, 1H), 6.69 (dd, 1H), 6.93-6.88 (m, 2H), 7.00 (dt, 1H), 7.10 (dd, 1H), 7.57-7.50 (m, 2H); MS (ESI/pos) m/z (rel intensity) 405.3 (100).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH3:18][O:19][C:20](=O)[O:21]C.[H-].[Na+]>C1COCC1>[C:20]([CH:15]1[CH2:16][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=2)[CH2:12][CH2:13][C:14]1=[O:17])([O:19][CH3:18])=[O:21]
Reactant: COC(=O)c1ccc(C2CCC(=O)CC2)cc1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CCC(=O)C(C(=O)OC)C2)cc1
Yield: 63 %

Procedure:
Compound 14 was acylated with dimethylcarbonate/NaH/-KH in THF to give 15 (63%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[Br:15]Br>CC(O)=O>[Br:15][CH:3]1[CH2:4][CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[S:9][C:10]=2[C:2]1=[O:1]
Reactant: BrBr
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Temperature: 75 °C

Procedure:
N-(7-Oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (Stage T.4, 2.286 g, 10.87 mmol) was dissolved in AcOH (60 ml), then bromine (1.74 g, 10.87 mmol) dissolved in AcOH (10 mL) were slowly added and the RM was heated to 75° C. for 20 h. The color changed from red to beige. The mixture was evaporated and the residue was dissolved in MeOH (10 mL) and precipitated with H2O. The mixture was filtered and dried on HV. The crude material was chromatographed with MPLC C18 H2O 0.1% TFA/CH3CN 0.1% TFA, gradient 0-50%. Fractions containing the product were neutralized with NaHCO3, extracted with EtOAc and lyophilized from dioxane to give of the title compound as a white solid (M+H=291; M−H=289; tR 4.29 (Method F)). 1H-NMR (d6-DMSO, 600.13 MHz) 12.75 (s, 1H) 4.95 (t, 1H), 2.95-2.84 (m, 2H), 2.62-2.52 (m, 1H), 2.40-2.30 (m, 1H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][C:14]=1[N+:27]([O-:29])=[O:28]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][C:14]=2[N+:27]([O-:29])=[O:28])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
24.5 ml (168 mmol) of 1-ethoxycarbonylpiperazine are added to a solution of 15.0 g (56 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 50 ml of dimethyl formamide and the solution is stirred at a reaction temperature of 100° C. for 3 hours. When the reaction mixture is cold, it is poured out on 300 ml of ice water with vigorous stirring. The precipitated solid is suction filtered, washed with a small quantity of ethanol and diethyl ether and recrystallized from 500 ml of ethanol. 16.7 g (76%) of orange yellow crystals, m.p. 140° to 142° C., are obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([S:16][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ncccc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1SCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To a solution of 3-bromo-2-methylpyridine (1.0 g) in toluene (12 mL) were added phenylmethanethiol (794 mg), N,N-diisopropylethylamine (1.65 g), tris(dibenzylideneacetone)dipalladium(0) (213 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (269 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 4 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give the title compound as a yellow solid (yield 742 mg, 59%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[B].[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][CH:33]=[CH:32][C:31]=1Br)(=[O:27])[CH3:26]>CO>[C:25]([O:28][CH2:29][C:30]1[C:31]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:32][CH:33]=[CH:34][C:35]=1[N:36]1[CH2:48][CH2:47][N:39]2[C:40]3[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=3[CH:46]=[C:38]2[C:37]1=[O:49])(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Agent: [B]
Solvent: CO
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 44.8 %

Procedure:
Following Example 306b, 307a (422 mg, 1.26 mmol) was converted to the boron intermediate 307b, which was coupled under Suzuki conditions with 109a (420 mg, 1.0 mmol). The crude product was purified via column chromatography: ISCO 24 g silica, 50-100% ethyl acetate/hexanes then 0-10% MeOH, to give 307c (285 mg, 36% yield).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:37]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:8]3[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:11]=[CH:10][N:9]3[C:13]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:24]=2)=[CH:21][CH:20]=1)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
To a solution of 4-{8-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl}phenol (110 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) was added allyl bromide (27 μL, 0.31 mmol) and cesium carbonate (160 mg, 0.48 mmol). The mixture was heated at 80° C. for 3 hours. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. The residue was purified by flash chromatography (1:1 ethyl acetate:hexanes) to give 2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-8-amine (40 mg, 34%) as a yellow foam. 1H NMR (CDCl3): δ 8.87 (d, 1H), 8.04 (d, 1H), 7.57 (d, 2H), 6.95 (d, 2H), 6.75 (t, 1H), 6.40 (d, 1H), 6.26 (d, 1H), 6.1 (m, 1H), 5.43 (d, 1H), 5.30 (m, 3H), 4.58 (d, 2H), 4.35 (m, 1H), 3.92 (m, 1H), 2.10–2.00 (m, 4H), 1.76–1.45 (m, 12H); MS m/z 495 (M+1).
Reaction SMILES: C[C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.CS(O)(=O)=O.[NH2:26]N1C=CC=N1>>[NH2:20][C:8]([NH:4][C:5]1[NH:26][N:3]=[CH:2][CH:6]=1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Nn1cccn1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)Nc2ccn[nH]2)cc1

Procedure:
The compound of Example 17 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-aminopyrazole solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 279.32; found mol. wt. (M+H) 280.3; 559.0 (Dimer)
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[CH3:14][NH2:15]>ClCCl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:15][CH3:14])(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(F)c(Br)cc1F

Procedure:
According to general procedure C, 4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol) and methylamine were stirred together in dichloromethane (1 mL) for 16 hours. The reaction afforded 4-bromo-2,5-difluoro-N-methylbenzenesulfonamide (0.17 g) after purification. HPLC purity 100.0% at 210-370 nm, 9.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C7H6BrF2NO2S−H+, 283.91979; found (ESI-FTMS, [M−H]1−), 283.92003
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[O:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J26) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.05 g).
Reaction SMILES: [F:1][C:2]1[C:3]([I:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[O:7][CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:28][O:29][NH:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[C:3]([I:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([N:30]([O:29][CH3:28])[CH3:31])=[O:14])[O:7][CH2:6][CH2:5]2
Reactant: CNOC
Reactant: O=C(O)C1OCCc2c1ccc(F)c2I
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1OCCc2c1ccc(F)c2I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-fluoro-5-iodo-3,4-dihydro-1H-isochromene-1-carboxylic acid (1.32 g, 4 mmol) and CDI (690 mg, 4.9 mmol) in 50 mL of dry DCM was stirred at r.t. for 3 hrs and then O,N-dimethyl-hydroxylamine (500 mg, 5.1 mmol) was added. The result mixture was stirred oversight. The solvents were removed under vacuum, and the residue was purified via column chromatograph to afford 6-fluoro-5-iodo-N-methoxy-N-methyl-3,4-dihydro-1H-isochromene-1-carboxamide.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[N:7][CH:8]=1.[I-:18].[K+]>CC(C)=O.C(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([CH2:2][I:18])[CH:4]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc(F)cc1)c1cncc(CCl)c1
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cncc(CI)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-chloromethyl-pyridin-3-yl)-(4-fluoro-phenyl)-methanone (1J) (220 mg, 0.88 mmol) in 5 mL of acetone at room temperature is added potassium iodide (590 mg, 3.6 mmol). After being stirred at room temperature for 3 hours, the reaction mixture is diluted with 50 mL of CH2Cl2 and washed with 5 mL of water. After concentration, the residue is dissolved in 15 mL of CH2Cl2 and washed with 2 mL of saturated sodium hyposulfite. After being dried, the solution was concentrate to give a 80/20 mixture (by 1H NMR) of (4-fluoro-phenyl)-(5-iodomethyl-pyridin-3-yl)-methanone (1F) and the starting chloride (1J) as light yellow solid that is used without further purification for next step reaction. MS (ESI) m/e 342 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[CH:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)[CH2:4][C:3]=1[O:15][CH3:16].[C:17]([Mg]Cl)([CH3:20])([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH3:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: COC1=C(Br)C=C2C(=O)CCC(C)(C)C2C1
Reactant: CC(C)(C)[Mg]Cl
Product: COc1cc2c(cc1Br)C(C(C)(C)C)=CCC2(C)C
Yield: 34 %

Procedure:
Following General Procedure A, 7-bromo-6-methoxy-4,4-dimethyl-dihydro-2H-naphthalen-1-one (Compound 92, 1.5 g, 5.3 mmol) was reacted with t-butylmagnesium chloride to afford 0.5743 g (34%) of the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][C:4]2[S:14][CH:15]=[CH:16][C:3]1=2.C1(C)C=CC=CC=1>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][C:4]2[S:14][CH:15]=[CH:16][C:3]1=2
Reactant: CCOC(=O)N1CCc2sccc2C(=O)C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)N1CCc2sccc2[C@H](O)C1

Procedure:
3.86 g (16.1 mmol) ethyl 4-oxo-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylate (prepared analogously to WO2007/84622) in 50 ml methylene chloride are combined, under argon, at −25° C., first with 1.92 ml of a 1.0 M toluene solution of (S)-3,3-diphenyl-1-methyl-tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolidine and then with 20.2 ml of a 2 M borane-dimethylsulphide complex-toluene solution in 70 ml methylene chloride, and chilled to −18° C. for 3 days. Then sat. NH3Cl solution is added and the mixture is extracted 3× with methylene chloride. The combined organic phases are dried with NaSO4, concentrated and the crude product is purified by flash chromatography on silica gel (eluant DCM/methanol 95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].Cl.[NH2:33][OH:34].CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:33][OH:34])=[NH:26])[CH:20]=3)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: NO
Reactant: N#Cc1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-{4-[(2-cyanopyridin-4-yl)oxy]phenyl}propanamide (0.300 g, 0.67 mmol), hydroxylamine hydrochloride (0.117 g, 1.69 mmol), and DIPEA (0.117 mL, 0.67 mmol) in MeOH was allowed to stir at rt overnight. The mixture was concentrated and purified by column chromatography to give A-85 (68 mg). 1H NMR (300 MHz, d6 DMSO) δ: 10.48 (br s, 1H), 10.17 (br s, 1H), 8.50 (d, 1H), 8.14-8.20 (m, 1H), 7.77-7.85 (m, 1H), 7.60-7.66 (m, 1H), 7.50-7.56 (m, 1H), 7.39-7.47 (m, 1H), 7.20-7.26 (m, 1H), 7.01-7.13 (m, 3H), 2.92-3.01 (m, 2H), and 2.65-2.72 (m, 2H). LCMS, FA: Rt=1.98 min, [MH+ 479.3].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:28]=[CH:27][C:13]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]1([C@H:68]([NH2:70])[CH3:69])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24]([NH:70][C@@H:68]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH3:69])=[O:25])=[CH:27][CH:28]=2)=[CH:7][CH:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a suspension of 4-{(R)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyric acid HCl salt (220 mg, 0.5 mmol, 1 eq.) in dichloromethane (5 ml) was added PyBrOP (280 mg, 0.6 mmol, 1.2 eq.), DIPEA (200 mg, 1.5 mmol, 3 eq.) and (R)-1-phenyl ethylamine (80 mg, 0.6 mmol 1.2 eq.). The mixture was stirred at room temperature overnight. The volatile material was removed under reduced pressure and the residue was purified by preparative TLC using dichloromethane/MeOH (15:1) as mobile phase (twice) followed by a column chromatography on silica gel using dichloromethane/MeOH (15:1) as eluent to give the desired product (12 mg, 5%); LCMS (UV, ESI), m/z 493 (M); HPLC: 99%.
Reaction SMILES: BrBr.[OH-:3].[Na+].[O:5]=[C:6](C)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>O>[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:5])=[O:3]
Reactant: CC(=O)CCCCn1c(-c2cccnc2)c(C)c2ccccc21
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Product: Cc1c(-c2cccnc2)n(CCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (0.344 ml) is added to a solution of 692 mg of sodium hydroxide in 4 ml of water with ice bath cooling. The resulting solution is added to 400 mg of 1-(5-oxohexyl)-3-methyl-2-(3-pyridyl)indole and this mixture is stirred for 2 hours at room temperature. The mixture is washed with ether. The aqueous solution is filtered and acidified to pH 5-6 with 2 N HCl. A crude white solid is collected which melts in the range 108°-120°. TLC (silica gel; methylene chloride/methanol 9:1) separation gives 1-(4-carboxybutyl)-3-methyl-2-(3-pyridyl)indole of Example 5.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1[CH:15]=CC=C[CH:11]=1>>[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:10]([CH3:15])[CH3:11])([CH3:9])[CH3:8]
Reactant: c1ccccc1
Solvent: CC(C)c1ccccc1
Product: CC(C)c1ccccc1C(C)C

Procedure:
In a preferred embodiment, as step (f), a make-up benzene stream is fed to a make-up benzene feed stage of the tower in fluid communication between the upper distillation zone below and a top distillation zone above. In a step (g), water is separated from the benzene condensed in step (e) to form a wet benzene stream. As step (h), the wet benzene stream from step (g) is refluxed to the top distillation zone. In a step (i), the bottom product from step (b) is preferably fed to a cumene column to obtain a cumene product stream essentially free of diisopropylbenzene and heavier benzene alkylates, and a bottoms stream comprising diisopropylbenzene and heavier benzene alkylates. In a step (j), the bottoms stream from step (i) is preferably fed to a diisopropylbenzene column to obtain a diisopropylbenzene stream essentially free of heavier benzene alkylates. As step (k), the propane stream from step (e) is contacted with the diisopropylbenzene stream from step (j) in an absorber to obtain a propane stream essentially free of benzene and a diisopropylbenzene stream containing benzene absorbed from the propane stream. The process can further comprise as step (l), compressing and cooling the propane stream from step (k) to form liquefied petroleum gas. The process can also comprise as step (m) feeding the benzene stream from step (c) to a heated side-stripper to form a dehydrated liquid benzene stream and a benzene vapor stream of enhances water content, and as step (n) returning the benzene vapor stream from step (m) to adjacent the side draw stage of step (c).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28](I)[C:27]([F:31])=[CH:26][N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:28]2[C:27]([F:31])=[CH:26][N:25]=[C:24]([Cl:23])[CH:29]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1cnc(Cl)cc1I
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Product: Cc1ccccc1C(CC(=O)c1cc(Cl)ncc1F)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 2-chloro-5-fluoro-4-iodopyridine (CAS RN: [659731-48-3]) was prepared the title compound as a white solid, MS (ESI−): m/z=430.0013 ([M−H]−, 1Br).