Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1.[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)ccc3o2)CC1
Yield: 21.1 %

Procedure:
Following the General Procedure-1, the titled compound (40 mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and Intermediate 3 (154 mg, 0.51 mmol) as an off-white solid. M.P.: 144-147° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.87 (s, 1H), 7.82 (d, J 8, 1H), 7.77 (dd, J 1.4, 9.4, 1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.15 (d, J 7.7, 2H), 3.22-3.10 (m, 4H), 3.00 (t, J 11.3, 2H), 2.21-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10]3=[O:17])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:25])[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>>[CH3:20][O:21][C:22](=[O:25])[CH2:23][N:11]1[C:10](=[O:17])[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=2)[C:12]1=[O:16]
Reactant: COC(=O)CBr
Reactant: O=C1NC(=O)c2cc(Oc3ccc(F)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CN1C(=O)c2ccc(Oc3ccc(F)cc3)cc2C1=O
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 5-(4-fluoro-phenoxy)-isoindole-1,3-dione (42.9 g, 167 mmol), Bromo-acetic acid methyl ester (21.1 ml, 223 mmol), K2CO3 (62.3 g, 446 mmol) and Et2CO (700 ml) was refluxed with stirring for 16 h before the mixture was concentrated in vacuo. To the residue was added water (150 ml) and the resulting slurry was extracted with EtOAc (1×750 ml, 1×250 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (49.7 g); 1H NMR (CDCl3) δ=7.80 (d, 1H), 7.01 to 7.30 (m, 6 H), 4.41 (s, 2 H), 3.76 (s, 3 H).
Reaction SMILES: [CH:1]([NH2:14])([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[C:16]1[NH:17][CH2:18][CH2:19][N:20]=1>C(OCC)C>[CH:1]([N:14]=[C:16]1[NH:20][CH2:19][CH2:18][NH:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC1=NCCN1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: c1ccc(C(N=C2NCCN2)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 2.26 g of benzhydrylamine and 30 ml of an ethyl ether solution containing 2.5 g of 2-chloro-2-imidazoline was allowed to stand at room temperature for 2 days. The reaction mixture was then treated in the same manner as in Synthesis Example 1 to give crystals of 2-benzhydryliminoimidazolidine. The crystals were dissolved in methanol and an equivalent amount of concentrated hydrochloric acid solution was added. The solution was distilled off in vacuo to give 3.2 g of 2-benzhydryliminoimidazolidine hydrochloride having a melting point of 207°-209° C.
Reaction SMILES: [F:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[OH-].[Na+]>>[F:1][C:2]1[CH:11]=[C:10]2[C:9]3[N:8]([CH:24]=[C:18]([C:19]([OH:21])=[O:20])[C:17]2=[O:16])[CH:7]([CH3:12])[CH2:6][CH2:5][C:4]=3[C:3]=1[Cl:13]
Reactant: CC1CCc2c(ccc(F)c2Cl)N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: CC1CCc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Yield: 54 %

Procedure:
A mixture of 1.5 g of 6-fluoro-5-chloro-1,2,3,4-tetrahydroquinaldine and 1.8 g of diethyl ethoxymethylenemalonate was heated at 160° C. for 30 minutes. Then, 14 g of polyphosphoric acid prepared from 7 g of phosphorus pentoxide and 7 g of phosphoric acid was added to the mixture and the resulting mixture was allowed to react by heating at 140° to 150° C. for 1 hour. After completion of the reaction, the reaction mixture was poured onto 100 g of ice, followed by adjusting the mixture to pH 6 to 7 with a 10 N aqueous sodium hydroxide solution. The precipitates were collected by filtration and added to 30 ml of concentrated hydrochloric acid followed by heating under reflux. After completion of the reaction 50 ml of water was added to the reaction mixture to precipitate crystals. The crystals thus-obtained were collected by filtration, washed with water and dried. Recrystallization of the crude crystals from ethanol gave 1.2 g of 9-fluoro-8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 297° to 298° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:10][CH:9]=1.C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32].O>ClCCl>[CH3:34][S:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[CH:14]=[CH:13][CH:12]=2)[CH:17]=1)(=[O:33])=[O:32]
Reactant: CC(=O)NCCc1cccc2ccc(OCCCCCO)cc12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1cccc2ccc(OCCCCCOS(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a 250 ml round-bottomed flask, dissolve the compound obtained in Step B (3.15 g, 10 mmol) in 50 ml of dichloromethane and add triethylamine (1.6 ml; 12 mmol). Cool in an ice/salt bath at 0° C, and then add mesyl chloride (0.93 ml; 12 mmol) dropwise with stirring using a magnetic stirrer. Allow the reaction mixture to return to room temperature and stir for 5 hours. Add 100 ml of water and extract the aqueous phase 3 times with dichloromethane. Wash the organic phase with 3×20 ml of an aqueous 1M hydrochloric acid solution and then with water, dry over magnesium sulphate and evaporate under reduced pressure. Purify the resulting oil by chromatography over silica gel (eluant: acetone/cyclohexane (3/7)). Colourless oil.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=O.CN(C=O)C.S(Cl)(Cl)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:8][C:9]1[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=1[C:11]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:38]=[N:37][N:36]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2Br)cc1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
Triethylamine (1.04 g; 10.38 mmol) was added to a mixture of 2-bromo-N-(4-nitrophenyl)benzamide (3 g; 9.35 mmol) in acetonitrile (12 ml) and DMF (0.189 g; 2.58 mmol) and the mixture was stirred for 90 minutes. Thionyl chloride (1.44 g; 12.14 mmol) was then added slowly keeping the reaction temperature below 25° C. The mixture was stirred for 5 hours at ambient temperature and then cooled to 10° C. Triethylamine (2.83 g; 28 mmol) was then added, followed by sodium azide (1.33 g; 20.4 mmol) and tetrabutylammonium bromide (0.42 g; 1.3 mmol). The mixture was stirred for 2 hours at 10° C. and then allowed to warm to ambient temperature and stirred for 24 hours. The mixture was poured into excess water and the precipitated solid collected by filtration. The solid was purified by trituration with a hot mixture of ethyl acetate (26 ml), hexane (2.6 ml) and triethylamine (0.1 ml) to give 5-(2-bromophenyl)-1-(4-nitrophenyl)-1H-tetrazole (B) (2.36 g; 73% yield) as an off-white solid; NMR (d6 -acetone; 270 MHz): 7.61-7.86(m, 6H), 8.41(d, 2H); microanalysis, found: C, 44.8; H, 2.1; N, 20.0; Br, 23.6%; C13H8BrN5O2 requires: C, 45.1; H, 2.3; N, 20.2; Br, 23.1%.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl.[CH2:24](O)[CH3:25]>>[CH2:24]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[CH2:6][CH:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: CCO
Reactant: CN(C)CCC(Cc1ccccc1C(=O)O)c1ccccc1
Agent: Cl
Product: CCOC(=O)c1ccccc1CC(CCN(C)C)c1ccccc1

Procedure:
A solution of 29.7 g. (0.1 mole) of 2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid in 200 ml. of ethanol is saturated with gaseous hydrochloride, and the resulting mixture is refluxed for 18 hours. The solvent is removed in vacuo and the residue is partitioned between ether and 2N sodium hydroxide. The ether extract is dried and evaporated in vacuo to give 2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:8]([O:21][CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:23](N)=O>>[CH3:22][O:21][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:1]=[CH:23][NH:6][C:4]2=[O:5]
Reactant: NC=O
Reactant: COc1cc(C(N)=O)c(N)cc1OCCOc1ccncc1
Product: COc1cc2c(=O)[nH]cnc2cc1OCCOc1ccncc1
Temperature: 50 °C
Yield: 49 %

Procedure:
5-Methoxy-2-nitro-4-(2-(4-pyridyloxy)ethoxy)benzamide (2.15 g, 6.4 mmol) and 10% palladium-on-charcoal catalyst (100 mg) were suspended in methanol (400 ml) and placed under hydrogen at atmospheric pressure. The reaction mixture was heated at 40° C. for 1 hour, cooled to ambient temperature, filtered through diatomaceous earth and the solvent was removed by evaporation. The precipitate was slurried with ether and collected by filtration to give 2-amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide as a cream solid (1.95 g, 99%). 2-Amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide (1.95 g, 6.4 mmol) and formamide (10 ml) were heated at 190-200° C. for 1 hour. The reaction mixture was allowed to cool to 50° C. as the product precipitated out. Water (50 ml) was added and the solid was collected by filtration, washed with more water and ether and dried under vacuum to give 6-methoxy-7-(2-(4-pyridyloxy)ethoxy)-3,4-dihydroquinazolin-4-one (0.99 g, 49%) as a cream solid. The 6-methoxy-7-(2-(4-pyridyioxy)ethoxy)-3,4-dihydroquinazolin-4-one (312 mg, 1 mmol) was heated at reflux in thionyl chloride (10 ml) and DMF (5 drops) for 1 hour, then evaporated to dryness and partitioned between a saturated solution of sodium hydrogen carbonate and methylene chloride. The methylene chloride phase was dried by filtration through a phase separator paper and the solvent was removed by evaporation to give crude 4-chloro-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CS([O-])(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[S:19][C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:26]=2[N:27]=1>C(Cl)(Cl)Cl>[NH2:17][C:18]1[S:19][C:20]2[CH2:21][CH2:22][N:23]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:24][CH2:25][C:26]=2[N:27]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: O=S(=O)([O-])CCCCCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CCCCCc1ccccc1)CC2
Yield: 19 %

Procedure:
Prepared from 5-phenyl-1-pentyl-mesylate and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 19% of theory, Melting point: 102°-105° C. (petroleum ether).
Reaction SMILES: [CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[C:7](=[O:8])[O:6]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:18].[K+].[K+].OO>CC(C)=O.O>[CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH2:16])=[O:18])=[CH:12][CH:13]=2)[C:7](=[O:8])[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCC1OC(=O)c2cc(C#N)ccc21
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCC1OC(=O)c2cc(C(N)=O)ccc21
Reaction time: 8 h

Procedure:
To a solution of 0.8 g (3.72 mmol) of compound obtained in Example 18 in 100 ml of acetone there is added a solution of 0.55 g of potassium carbonate in 5 ml of water, to which there are added, at 20° C., 14 ml of 30% hydrogen peroxide. The mixture is put aside at room temperature overnight. The solvents are removed in vacuo and the residue is washed with water and crystallised from ethanol, giving the title compound.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[N:56]=[C:55]([C:57]3[CH:62]=[CH:61][N:60]=[C:59](Cl)[CH:58]=3)[CH:54]=[CH:53][N:52]=2)[CH:47]=[CH:48][CH:49]=1.[CH3:64][C@@H:65]1[CH2:69][O:68][C:67](=[O:70])[NH:66]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[Cl:43][C:44]1[CH:45]=[C:46]([NH:50][C:51]2[N:56]=[C:55]([C:57]3[CH:62]=[CH:61][N:60]=[C:59]([N:66]4[CH:65]([CH3:64])[CH2:69][O:68][C:67]4=[O:70])[CH:58]=3)[CH:54]=[CH:53][N:52]=2)[CH:47]=[CH:48][CH:49]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1COC(=O)N1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 120 °C

Procedure:
A solution of Xantphos (0.018 g) and Pd2(dba)3 (0.014 g) in toluene (2 ml) is stirred under argon at room temperature for 20 minutes. Then (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (0.20 g), (R)-4-methyl-oxazolidin-2-one (0.127 g), NaOtBu (0.085 g) and toluene ((2 ml) are added. The reaction mixture is refluxed at 120° C. for 1 hour. After this time the mixture is cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer is dried over Na2SO4 and concentrated under vacuum. The residue is purified by silicagel chromatography to give the title compound, m.p. 177–178° C. and [α]D=−72.0° (20° C., c=1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 0.33 h
Yield: 20 %

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (0.955 g, 4.80 mmol) in 2 mL of DMF at 0° C. was added NaH (60% in oil, 0.349 g, 8.72 mmol) in one portion. After stirring for 20 min, 2,4,5-trichloropyrimidine was added. The mixture was stirred at 0° C. for 30 minutes, and then at room temperature for 2 h. After quenching with saturated ammonium chloride solution, the mixture was poured in water and ethyl acetate mixture. Yellow suspension was filtered as final product (0.3 g, 20% yield). MS/ES+: m/z=346.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:15]=1[O:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>>[Cl:34][C:32]1[CH:31]=[CH:30][C:15]([O:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:33]=1
Reactant: CCN(CC)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CCN(CC)C(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product from Example 129b (199 mg, 0.62 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (49.2 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.01 (s, 6H) 2.73 (s, 3H) 3.35 (s, 1 H) 3.53-3.81 (m, 4 H) 6.70 (d, J=7.35 Hz, 1 H) 6.93 (d, J=8.46 Hz, 2 H) 7.22 (d, J=8.82 Hz, 2 H) 7.34 (d, J=8.82 Hz, 1 H) 7.62 (dd, J=8.82, 2.57 Hz, 1 H) 7.73 (d, J=6.25 Hz, 1 H) 7.75 (s, 1 H) 8.53 (d, J=6.99 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H) 10.92 (s, 1 H) 14.55 (s, 1 H); MS (ESI+) m/z 461 (M+H−TFA)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C:54]([NH:56][CH2:57][CH2:58][CH2:59][C@H:60]([NH2:71])[C:61]1[NH:65][C:64]2[CH:66]=[CH:67][C:68]([Cl:70])=[CH:69][C:63]=2[N:62]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50].ClCCl.CO.N.ClCl>O1CCCC1>[C:49]([O:53][C:54]([NH:56][CH2:57][CH2:58][CH2:59][C@H:60]([NH:71][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:61]1[NH:65][C:64]2[CH:66]=[CH:67][C:68]([Cl:70])=[CH:69][C:63]=2[N:62]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 82 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-4-(tert-butoxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)butylamine in tetrahydrofuran. Yield: 82%; Rf value: 0.60 (silica gel; dichloromethane/methanol/ammonia=95:5:0.1); C29H36ClN5O4 (554.09); mass spectrum: (M+H)+=554/556 (chlorine isotope).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH2:22]Cl)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH3:17]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 100 °C
Yield: 79.1 %

Procedure:
10 g of p-hydroxybenzophenone are dissolved in 100 ml of dimethylformamide. 8.3 g of 2-chloroethylcarbamic acid ethyl ester and 13.8 g of potassium carbonate are added to the solution and the mixture is warmed to 100° C. and maintained there for 3 hours with stirring. The mixture is poured onto an ice/water bath. The resulting crystals are filtered and washed with water. The crystalline substance is dried at 40° C. in a vacuum drying oven. Recrystallization once from ether yields 12.5 g (80%) of 2-(p-benzoylphenoxy)ethylcarbamic acid ethyl ester, m.p.--84°-86° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OCCO2)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].Br[C:18]([C:20]([F:23])([F:22])[F:21])=[CH2:19].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]([C:20]([F:23])([F:22])[F:21])=[CH2:19])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: C=C(Br)C(F)(F)F
Reactant: Fc1ccc(B2OCCO2)cc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 70 °C
Yield: 23.2 %

Procedure:
The mixture of 2-(4-fluoro-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (2.34 g, 10 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (2.10 g, 12 mmol), Pd(Ph3P)2Cl2 (0.281 g, 0.4 mmol) and K2CO3 (2.76 g, 20 mmol) in THF (30 mL) and H2O (15 mL) was heated at 70° C. overnight. Then the reaction mixture was cooled down to rt, added water and extracted with ethyl acetate, washed with brine, dried with Na2SO4, concentrated to dryness to afford the crude product. It was further purified by column chromatography eluted with PE to afford the desired product (0.6 g, yield 23.3%) as light yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.69-7.62 (m, 2H), 7.27-7.21 (t, 1H), 6.05 (d, 1H), 5.80 (d, 1H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].I[CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: CS(=O)(=O)CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(CCCS(C)(=O)=O)S(C)(=O)=O)c(I)cc12
Reaction time: 0.33 h
Yield: 53 %

Procedure:
2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (162 mg, 0.331 mmol), 1-iodo-3-(methylsulfonyl)propane (82 mg, 0.331 mmol) and cesium carbonate (119 mg, 0.364 mmol) in DMF (1656 μL) are heated for 20 min at 150° C. by microwave. 3:1 Product/starting material. An additional 45 mg of alky iodide are added and 60 mg of cesium carbonate and heated for 20 min at 150° C. by microwave. LCMS indicates complete consumption of starting material. Acetonitrile and water are added and the mixture is filtered with 0.45μ PTFE filter. Purification is achieved by reverse phase HPLC with a C8 column with 20-50% ACN//H2O (0.1% NH4OH) over 20 min. Elutes at 13-15 minutes to give the title compound (107 mg, 53%). MS (ESI) m/z 610.0 (M+1). Retention time=1.40 min, Method A.
Reaction SMILES: Br[C:2]1[C:3]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=2)=[CH:4][C:5]([F:30])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.CCOC(C)=O>C1COCC1.CC(O)=O.O.[Zn]>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:3]2[CH:2]=[CH:7][C:6]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)(=[O:10])=[O:9])=[C:5]([F:30])[CH:4]=2)=[CH:33][C:34]=1[F:40])#[N:39]
Reactant: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2cc(Br)c(Oc3ccc(C#N)c(F)c3)cc2F)c(OC)c1
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc(Oc2ccc(S(=O)(=O)Nc3ccc(F)cn3)c(F)c2)cc1F
Temperature: 25 °C
Reaction time: 70 h
Yield: 11.3 %

Procedure:
To a solution of 5-bromo-4-(4-cyano-3-fluorophenoxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 1, 220 mg, 0.35 mmol) in THF (8 mL), AcOH (10 mL) and water (2.5 mL) was added zinc dust (800 mg, 12.2 mmol). The reaction mixture was left to stir at room temperature for 70 hours. To the reaction mixture was added EtOAc (25 mL) and the mixture filtered through celite and washed with EtOAc (50 mL). The filtrate was retained and to this was added saturated aqueous NaHCO3 (80 mL). The organic layer was retained, dried over MgSO4, and the solvent removed in vacuo. The residue was purified using reverse phase column chromatography eluting with acetonitrile and water (acidic). The residue was dissolved in DCM and treated with TFA (0.3 mL) and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo azeotroping with MeOH. The residue was purified using preparative HPLC to afford the title compound as a colourless powder (16 mg, 26%).