Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH2:15][Cl:16]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][Cl:16])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: ClCCn1cc(Br)cn1
Temperature: 60 °C
Yield: 87.1 %

Procedure:
4-Bromopyrazole (700 mg, 4.76 mmol, available from Aldrich), cesium carbonate (2328 mg, 7.14 mmol, available from Aldrich) and 1-bromo-2-chloroethane (0.592 ml, 7.14 mmol, available from Acros) were suspended in N,N-dimethylformamide (DMF) (14 ml) and heated to 60° C. under microwave conditions in an Emrys Optimiser for 1 hour. The mixture was partitioned between water (20 ml) and ethyl acetate (60 ml). The aqueous layer was run off and the organic washed (water ×3 (10 ml), brine (10 ml)), dried (magnesium sulfate) and evaporated to dryness to give the desired compound (868 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1.[OH-].[Na+].[CH3:18][NH:19][CH2:20][CH3:21]>O>[CH3:18][N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH2:20][CH3:21]
Reactant: CCNC
Reactant: ClCCCCCCOc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(C)CCCCCCOc1ccc(Br)cc1
Temperature: 40 °C
Yield: 80 %

Procedure:
A 100 mL flask provided with a stirrer and a reflux condenser was charged in a nitrogen gas atmosphere with 14.6 g (0.05 mol) of the p-(6-chlorohexyloxy)bromobenzene, synthesized at the above-mentioned step 1), 4.0 g (0.10 mol) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 0.8 g (0.012 mol) of n-tetrabutylammonium bromide (available from Kanto Chemical Co., Inc.) and 5.0 g of water. The content was maintained at 40° C. while being stirred. Then 5.9 g (0.10 mol) of methylethylamine (available from Wako Pure Chemical Industries Ltd.) was dropwise added at the same temperature over a period of 2 hours. Thereafter the reaction liquid was maintained at that temperature for 20 hours while being stirred. After completion of the reaction, the phase separation was conducted and the organic phase was subjected to silica-gel column chromatography to give 13.4 g of the target p-(N-methyl-N-ethylaminohexyloxy)bromobenzene (yield: 80%, purity: 94%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C[O:40][CH2:39]C1>>[CH:39]([CH:33]1[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31][CH2:32]1)=[O:40]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15.9 mL of LDA (2 M solution in THF) in 25 mL of THF at −78° C. was added 36.6 mL of diisopropylamine followed by 15.9 ml of (trimethylsilyl)diazomethane dropwise. After stirring at −78° C. for 30 min, 5.25 g of tert-butyl-4oxo-1-piperidinecarboxylate in 10 mL of THF was added slowly over 10 min. The reaction was stirred at −78° C. for 1 hr. After refluxing for 4 hr, the reaction was quenched with cold water and extracted with 3×70 mL of EtOAc. The combined organic phases were dried over MgSO4 and concentrated. The residue was dissolved in 150 mL of EtOAc, then 10 g of silica gel was added. After stirring at rt for 16 hr, silica gel was filtered off. Concentration of filtrate followed by flash chromatography eluting with 25% EtOAc in hexane followed by 100% EtOAc afforded 3.66 g of the title compound as an oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([CH3:31])([S:22]([C:25]1[CH:29]=[CH:28][O:27][C:26]=1[CH3:30])(=[O:24])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)C>C(O)C.[OH-].[Na+]>[CH3:31][C:5]([S:22]([C:25]1[CH:29]=[CH:28][O:27][C:26]=1[CH3:30])(=[O:24])=[O:23])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:8]=1)[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCN2CCCCC2)cc1)S(=O)(=O)c1ccoc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1occc1S(=O)(=O)C(C)(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)O

Procedure:
2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid was prepared according to the general method as outlined in example 1. Starting from 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester (2.01 g, 4.5 mmol), dissolved in ethanol (20 mL) and 10 N sodium hydroxide (10 mL). The resulting mixture was worked up as outline in example 9. Yield 2.03 g, amber crystals mp 66-68° C.; MS 434 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][N:13]2[CH2:17][CH2:16][CH:15](N(CC)CC)[CH2:14]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CC[N:25]([CH:29]([CH3:31])C)[CH:26]([CH3:28])C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:56][C:57]1[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH:17]2[N:25]([CH2:26][CH3:28])[CH2:29][CH3:31])[C:9]([NH:63][C:60]2[CH:61]=[CH:62][C:57]([Cl:56])=[CH:58][CH:59]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCN(CC)C1CCN(CC(C(=O)O)c2ccc(Br)cc2)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C1CCCN1CC(C(=O)Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromo-phenyl)-3-(3-diethylamino-pyrrolidin-1-yl)-propionic acid (590 mg, 1.6 mmol), DIPEA (1.03 g, 8 mmol), and Pybrop (1.12 g, 2.4 mmol) in CH2Cl2 (10 mL) was added 4-chloro-phenylamine (306 mg, 2.4 mmol). This mixture was stirred overnight at room temperature and then evaporated. The mixture redissolved in EtOAc (20 mL) and washed with water, brine, dried with Na2SO4, concentrated in vacuo. The residue was purified by flash column chromatography to give a white solid. MS: calc'd 478 (MH+), exp 478 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH:5]([NH:14][CH3:15])[C:6]1[CH:11]=[CH:10]C(OC)=C[CH:7]=1.[C:20]([O:28][CH2:29][CH3:30])(OCC)(OCC)C.[C:31](O)(=O)[CH3:32]>>[CH3:31][C:32]1[N:14]([CH3:15])[CH:5]([C:6]2[CH:7]=[CH:30][C:29]([O:28][CH3:20])=[CH:10][CH:11]=2)[CH2:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[N:1]=1
Reactant: CC(=O)O
Reactant: CNC(Cc1ccccc1N)c1ccc(OC)cc1
Reactant: CCOC(C)(OCC)OCC
Product: COc1ccc(C2Cc3ccccc3N=C(C)N2C)cc1
Temperature: 112 °C
Reaction time: 8 h

Procedure:
A stirred solution of 4.10 g of 2-amino-α-(4-methoxyphenyl)-N-methylphenethylamine, 16.22 g of triethyl orthoacetate and 5.6 ml of glacial acetic acid is held under reflux (bath temperature 112° C.) for 2 hours. After standing overnight at ambient temperature the solution is concentrated in vacuo (pump) at 90° C. on a rotary evaporator. An ethereal solution of the residual oil is washed with 5% hydrochloric acid. The aqueous phase is made alkaline with 50% sodium hydroxide solution and the mixture is extracted twice with 25 ml-portions of methylene chloride. The combined, (dried over anhydrous sodium sulfate) organic phase is evaporated to afford a solid. Recrystallization from 10 ml of acetonitrile provides tan crystals, mp 130°-132° C. of 4,5-dihydro-2,3-dimethyl-4-(4-methoxyphenyl)-3H-1,3-benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:22][N:23]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN.CCO>C(Cl)Cl>[CH3:22][NH:23][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:11]
Reactant: CC1CCC(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](CC1CCC(C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 46.7 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-3-(4-methylcyclohexyl)propanoic acid (2.080 g, 7.29 mmol, 1.0 equiv), EDC.HCl (3.308 g, 2.37 equiv), HOBt (1.752 g, 1.78 equiv), DIEA (7.6 mL, 6 equiv) and 33% wt. methylamine in EtOH (2.771 g, 4 equiv) in CH2Cl2 (80 mL) was stirred at rt for 21 h. The solvents were removed in vacuo and 1 N aq HCl (200 mL) was added. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 13 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 3.5 min, flow rate 25 mL/min) to give tert-butyl (S)-1-(methylcarbamoyl)-2-(4-methylcyclohexyl)-ethylcarbamate (1.0167 g, 47%). LC-MS (3 min) tR=1.72 min, m/z 321 (M+Na+), 243, 199; 1H NMR (400 MHz, CDCl3) δ 6.27 (br s, 1H), 4.91 (br s, 1H), 4.11-4.07 (m, 1H), 2.802, 2.798 (d, J=4.8 Hz, 3H), 1.85-1.20 (m, 21H), 0.886, 0.851 (d, J=6.4 Hz, 3H).
Reaction SMILES: C([N:8]1[C:20]2[C:19]([OH:21])=[C:18]3[N:22](C(OC(C)(C)C)=O)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:37])[CH:13]=2)(OC(C)(C)C)=O.Cl.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]Cl.C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>CC(C)=O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:18]1[C:19]([O:21][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[C:20]3[NH:8][C:9]4[CH:10]=[CH:11][C:12]([F:37])=[CH:13][C:14]=4[C:15]3=[CH:16][C:17]2=1
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A mixture of 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (406.8 mg, 0.8 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (126.8 mg, 0.88 mmol) and K2CO3 (10 equivalents) in 4A-molecular-sieve-dried acetone (40 mL) was magnetically stirred and heated to reflux under Ar. After the reaction was complete, it was cooled to room temperature. The inorganic salt was removed by filtration and washed with a small quantity of acetone. The combined acetone solution was concentrated on a rotavapor and dried under vacuum pump. The crude product was purified by flash chromatography. The resultant product 2-(2,10-difluoro-5,7-diBOC-indolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine was dissolved in CH2Cl2 (40 mL), and trifluoroacetic acid (˜40 equivalents) was added. The reaction was stirred at room temperature overnight, concentrated, and dried under vacuum pump. The crude compound was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO3 solution, dried under Na2SO4, concentrated, and flash chromatography to provide the desired product 2-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (195.9 mg, 65%). 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.40 (s, 2 H), 8.56 (s, 1 H), 7.87 (dd, J=9.2, 2.4 Hz, 2 H), 7.44 (dd, J=8.4, 4.4 Hz, 2 H), 7.20-7.11 (m, 2 H), 4.30 (t, J=5.8 Hz, 2 H), 2.72 (t, J=5.8 Hz, 2 H), 2.32 (s, 6 H); MS (ESI) m/z 378.1 (M−H)−; MS (ESI) m/z 380.1 (M+H)+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH:6][CH:7]1[CH2:13][CH:12]2[N:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=3)[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.[I-].[Na+].ClCCl>C(OCC)(=O)C>[ClH:1].[C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([N:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:8][CH:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH2:13]3)=[CH:16][CH:17]=1)#[N:26]
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(N2C3CCC2CC(NC(=O)CCCl)C3)c2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cl
Product: N#Cc1ccc(N2C3CCC2CC(NC(=O)CCn2ccnc2)C3)c2ccccc12
Yield: 43.2 %

Procedure:
165RL50 (61 mg, 0.17 mmol), imidazole (53 mg, 0.83 mmol), sodium iodide (10 mg, 0.07 mmol) and dichloromethane (6 mL) were shaken in a vial at 80° C. for 2 days. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (2×10 mL). The organic solution was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography using a stepwise gradient of 10-100% methanol in ethyl acetate to give the title compound (32 mg, 47%).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13](CC)[C:14](=[O:16])[O-])(=[O:12])=[O:11].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=1>ClC1C=CC=CC=1>[F:19][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=1)=[O:16])(=[O:11])=[O:12]
Reactant: CCN(C(=O)[O-])S(=O)(=O)c1ccccc1OC(F)F
Reactant: COc1nc(C)nc(N)n1
Solvent: Clc1ccccc1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1

Procedure:
A solution of 1.48 g of N-(2-difluoromethoxy-phenylsulfonyl)-ethylcarbamate and 0.62 g of 2-amino-4-methoxy6-methyl-1,3,5-triazine in 20 ml of chlorobenzene is refluxed. After concentration of the yellow solution by evaporation, and chromatographical purification of the residue, there is obtained a colourless oil which crystallises from an acetone/diethyl ether mixture by the addition of hexane. The yield is 0.45 g (23.1% of theory) of N-(2-difluoromethoxyphenylysulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, m.p. 140°-141° C.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH3:28][O:29][CH2:30][CH:31]1[CH2:33][O:32]1>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:33][CH:31]([OH:32])[CH2:30][O:29][CH3:28])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: COCC1CO1
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(O)COC)ccc-2c(C(=O)OCC)c1N
Yield: 15 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 2-methoxymethyl-oxirane the title compound is obtained in 15% yield as a wax.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1>C(#N)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CS
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CSCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a solution of ethyl 2-mercaptoacetate (Aldrich, 1.0 mL, 9.1 mmol) in acetonitrile (10.0 mL) were added K2CO3 (2.76 g, 20.0 mmol) and 1-(bromomethyl)-4-fluorobenzene (2.27 g, 12.0 mmol). The mixture was stirred at room temperature for 12 h. After filtration and concentration, the residue was purified by flash column chromatography on SiO2 to give ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 91% yield). MS(ESI+): m/z 251.08 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33](Br)(Br)([Br:35])[Br:34]>C1COCC1>[Br:34][C:33]([Br:35])=[CH:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][C:2]([CH3:13])([CH3:1])[C:6]=2[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)COc2ccc(C=O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(C=C(Br)Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 3,3-dimethyl-2,3-dihydro-1-benzofuran-5-carbaldehyde (4.18 g, 23.7 mmol) and triphenylphosphine (15.5 g, 59.3 mmol) in THF (40 mL) was added carbon tetrabromide, and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=49:1 to 7:3) to give the title compound (5.75 g, yield 73%) as an oil.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].O>C(OCC)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[Cl:12])[C:4](=[O:5])[CH2:3][Br:1]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)c(Cl)c1

Procedure:
Bromine in a quantity of 10.2 ml (0.2 mol) is added dropwise to a mixture of 37.8 g 3.4-dichloroacetophenone and approx. 1.0 g anhydrous AlCl3 in 600 ml dry diethylether while stirring and cooling in ice. After stirring for 0.5 hr at 0° C. and 1.5 hr at room temperature, 30 ml water are added slowly. The organic phase is separated, washed twice with water, dried and evaporated to dryness. A small amount of petroleum ether (40-60) is added to the residue and the mixture is stirred at approx. 0° C. The desired 3.4-dichlorophenacylbromide is obtained as a crystalline material in a yield of 39.8 g (74%); melting point 55°-58° C.; TLC (CH2Cl2)=0.5.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:13][CH:11]([S:8]([NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])(=[O:10])=[O:9])[CH3:12]
Reactant: CC(C)S(=O)(=O)NC1CCCC1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCCC1=O
Temperature: -55 °C
Reaction time: 0.03 h
Yield: 72.7 %

Procedure:
Scheme IA, step C: Into a flame dried 500 mL 3 neck flask fitted with a thermometer and magnetic stirrer, DMSO (6.16 mL) in methylene chloride (20 mL) was added dropwise to oxalyl chloride (3.80 mL) in methylene chloride (100 mL) while stirring at −55° C. under a nitrogen atmosphere. After 2 minutes, (2-hydroxycyclopentyl)[(methylethyl)sulfonyl]amine (8.00 g, 38.6 mmol) in methylene chloride (45 mL) was added dropwise at this temperature and the reaction was stirred for an additional 15 minutes. Triethylamine (25.5 mL) was then added dropwise and the reaction was allowed to warm to room temperature. 180 mL of water was added at room temperature and the layers were separated. The organic layer was washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 7.83 g as a dark oil. This material was purified via silica gel chromatography employing the Water's Prep. 2000 and eluting with a solvent of methylene chloride/ethyl acetate 9:1 to provide the intermediate title compound (5.76 g, 73%) as a yellow oil. Ion Spray M.S. 204.1 (M*−1). Calculated for C8H15NO3S: Theory: C, 46.81; H, 7.37; N, 6.82. Found: C, 46.56; H, 7.32; N, 6.77.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18](B(O)O)=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:17][N:16]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: O=Cc1cnc2ccc(Br)cn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(-c2ccc3ncc(C=O)n3c2)c(OC)n1
Yield: 47.43 %

Procedure:
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (Compound of step 1 of Intermediate 1, 200 mg, 0.89 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (212.57 mg, 1.15 mmol), dichlorobis(triphenylphosphine) palladium (II) (20 mg, 10% mmol) and 2M aqueous Na2CO3 (1 mL) were added to DMF (8 mL) and refluxed for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with H2O and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 47.43%; 1H NMR (DMSO-d6; 300 MHz): δ 9.97 (s, 1H), 9.59 (s, 1H), 8.56-8.58 (d, 2H, J=4.5 Hz), 7.88-7.98 (m, 2H), 3.96 (s, 3H), 3.98 (s, 3H); MS: m/z 285.1 (M+1)+
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1)[CH3:42]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M140) (0.34 g, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (239 mg, 87%).
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]([NH:21][C:22]([C:24]3[C:32]4[O:31][CH2:30][O:29][C:28]=4[CH:27]=[CH:26][C:25]=3[Br:33])=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C:40](N)(=O)C1C=CC=CC=1.[H-].[Na+].CI>CN(C=O)C.CCOCC>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]([N:21]([CH3:40])[C:22]([C:24]3[C:32]4[O:31][CH2:30][O:29][C:28]=4[CH:27]=[CH:26][C:25]=3[Br:33])=[O:23])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1cc2c(NC(=O)c3c(Br)ccc4c3OCO4)ccc(-c3ccc(-c4ccccc4)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc2c(-c3ccc(-c4ccccc4)cc3)ccc(N(C)C(=O)c3c(Br)ccc4c3OCO4)c2cc1OC

Procedure:
To a suspension of benzamide N-(4-(biphenyl-4-yl)-6,7-dimethoxynaphthalen-1-yl)5-bromobenzo[1,3]dioxole-4-carboxamide (1 mmol), and NaH (3 mmol) in dry DMF (20 mL) was added MeI (2 equiv). The reaction mixture was stirred over night, diluted with ether and then washed with 10% HCl and brine. The residue was subjected to column chromatography on silica using 2% methanol in chloroform to provide product N-(4-(biphenyl-4-yl)-6,7-dimethoxynaphthalen-1-yl)5-bromo-N-methylbenzo[1,3]dioxole-4-carboxamide as an off white solid. 1H NMR (400 MHz) (CDCl3) δ 3.39-3.60 (m, 3H, N—CH3), 3.66-3.80 (m, 3H, O—CH3), 3.96-4.00 (m, 3H, O—CH3), 5.03-6.18 (m, 2H, O—CH2O), 6.30-7.69 (m, 15H, aromatic).