Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH:4]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])[C:6](=[O:19])[CH2:5]1)#N.ClCCl.[CH2:23]([OH:25])[CH3:24].Cl.CC[O:29]CC>>[CH3:18][O:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[CH2:8][N:7]1[C:6](=[O:19])[CH2:5][CH:4]1[CH2:3][C:1]([O:25][CH2:23][CH3:24])=[O:29]
Reactant: CCO
Reactant: COc1ccc(CN2C(=O)CC2CC#N)c(OC)c1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CC1CC(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 8 h
Yield: 8.2 %

Procedure:
To a solution of 5.2 g (20 millimoles) of 4-cyanomethyl-1-(2,4-dimethoxy-benzyl)-2-azetidinone prepared according to the preceding paragraph in 40 ml of anhydrous ether and 40 ml of anhydrous dichloro methane 1.24 ml (21.2 millimoles) of ethanol are added and into the solution gaseous hydrogen chloride developed from 80 ml of concentrated aqueous hydrochloric acid is introduced under stirring and ice-cooling. The mixture is allowed to stand in a refrigerator overnight, the solution is evaporated to dryness and the residue is dissolved in about 25 ml of water. The pH of the aqueous solution is adjusted to 7 by adding a 10% aqueous sodium hydroxide solution and the solution thus obtained is allowed to stand overnight. The mixture becomes blue and the precipitated white crystals are filtered off. The aqueous filtrate is extracted five times with 10 ml of ether each. The united etheral phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. The residual oil (1 g) is separated by means of preparative thin layer chromatography (adsorbent: Kieselgel PF254+366 ; develop agent: n-heptane-acetone 7:3). Thus 0.501 g of ethyl [1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidinyl]-acetate is obtained. Yield: 8.2%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([Cl:10])=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2ccc(Cl)c(C(F)(F)F)c2)nc1Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-trifluoromethylaniline were reacted to yield N2,N4-bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.05 (bs, 1H), 7.89 (bd, 1H), 7.77 (dd, 1H, J=2.4 and 9 Hz), 7.65 (dd, 1H, J=2.4 and 8.7 Hz), 7.49 (d, J=8.1 Hz), 7.40 (d, 1H, J=6.2 Hz), 7.03 (s, 1H), 6.91 (s, 1H); 19F NMR (CDCl3): δ−17864 (s, 3F), −17894 (s, 3F), −46550 (s, 1F); LCMS: ret. time: 38.81 min.; purity: 75%; MS (m/e): 485 (MH+).
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=O.[O-:31][C:32]#[N:33].[Na+]>C(#N)C.O.C(O)(=O)C>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[NH:33][C:32](=[O:31])[N:6]([CH:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[CH:21]=2)=[CH:25][CH:26]=1
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ccc(-c2cn(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium acetate (41 mg, 0.50 mmol) was added to a solution of t-butyl 4-aminopiperidine-1-carboxylate (100 mg, 0.50 mmol) in acetonitrile (2 mL) at 0° C. After 5 min, 2-bromo-4′-methylacetophenone (106.4 mg, 0.50 mmol) in acetonitrile (1 mL) was added and the mixture was allowed to warm to ambient temperature. After 1.5 h, sodium cyanate (97.4 mg, 1.5 mmol), acetic acid (100 uL) and water (80 uL) were added to the reaction mixture. After 16 h, the mixture was concentrated to give the title compound.
Reaction SMILES: [C:1]1([C:7](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:38].[OH-]>O>[C:1]1([C:7](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([NH2:38])=[O:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(OCC(=O)O)cc2)CC(C)(C)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(OCC(N)=O)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To a solution of 34 (100 mg, 0.26 mmol) and CH2Cl2 (mL) was added oxalyl chloride (90 uL, 1.06 mmol) and the mixture was stirred at RT for 2 h. To this solution 10 mL of NH4OH (30% aqueous) was slowly introduced and stirred for 6 h. The mixture was poured into H2O (100 mL) and then extracted with EtOAc (2×100 mL). The organic layer was worked-out to give the crude product, which upon purification gave 11 mg (11%) of the desired product 35 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.48 (br s, 1H), 7.35 (br s, 1H), 7.27 (app. J=7.6 Hz, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.2 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.36 (s, 2H), 1.91 (s, 2H), 1.87 (s, 2H), 1.25 (s, 2H), 0.88 (s, 6H), 0.87 (s, 6H). LCMS (ESI): m/z 378 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[O:17].[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.CC([O-])=O.[K+]>>[Cl:12][C:10]1[N:9]=[CH:8][C:7]2[O:13][C:14]3[C:4]([C:5](=[O:17])[C:6]=2[CH:11]=1)=[CH:3][C:2]([C:24]1[C:19]([F:18])=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][CH:15]=3
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Product: O=c1c2cc(-c3cccnc3F)ccc2oc2cnc(Cl)cc12
Temperature: 120 °C

Procedure:
A vial was charged with 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (3 g, 9.66 mmol), 2-fluoropyridin-3-ylboronic acid (1.497 g, 10.63 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(H) (0.684 g, 0.966 mmol), and KOAc (1.510 mL, 24.15 mmol). The vial was evacuated and backfilled with nitrogen (this procedure was repeated twice). ACN (20 mL), dioxane (30 mL) and water (3 mL) were added, and the vial was sealed and the reaction mixture was heated to 120° C. for 4 h. The reaction mixture was cooled to RT. Upon addition of EtOAc, a solid precipitated which was filtered off and dried under vacuum to provide 3-Chloro-7-(2-fluoropyridin-3-yl)-5H-chromeno[2,3-c]pyridin-5-one as a tan solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([SH:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].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.CCN(C(C)C)C(C)C>O1CCOCC1.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]>[CH:21]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[N:11]([CH2:12][CH2:13][O:14][C:5]4[CH:4]=[C:3]([CH3:25])[C:2]([S:35][CH:32]5[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]5)=[CH:24][C:6]=43)[CH:10]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(C)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 64.2 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (146 mg, 0.363 mmol), 1-isopropylpiperidine-4-thiol (87 mg, 0.545 mmol), Pd2(dba)3 (17 mg, 5 mol %), XantPhos (21 mg, 10 mol %) and DIPEA (254 μl, 1.45 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 2 h using microwave irradiation. The reaction mixture was then diluted with DCM (80 mL) and purified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM) followed by (C18, gradient 20-55% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless solid (112 mg, 64%). LCMS: RT 2.23 and 2.28 min [M+H]+ 480.9
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[N:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[CH3:31][PH:32](=[O:34])[CH3:33]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[N:27][C:22]([P:32]([CH3:33])([CH3:31])=[O:34])=[CH:23][CH:24]=2)[CH:3]=1)[CH3:11]
Reactant: C[PH](C)=O
Reactant: OB(O)c1ccc(Br)nc1
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 6-bromo-3-pyridinylboronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 454 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37]C)=[O:36])=[CH:4][CH:3]=1.COC(=O)C(C)(C)CC1N(CC2C=CC(Cl)=CC=2)C2C(C=1SC(C)(C)C)=CC(OC)=CC=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([OH:37])=[O:36])=[CH:41][CH:42]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
Using the hydrolytic procedure of Step B but substituting the ester of Step D for the ester of Step A provided the title compound, which was recrystallized from 1:1 EtOAc/hexane. m.p. 208° C.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:46])[CH:22]=2)(OC(C)(C)C)=O.O[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Br:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Br:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: OCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: c1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]c3c(OCCN4CCOCC4)c4[nH]c5ccc(Br)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dibromo-6-hydroxyindolo[2,3-b]carbazole and the reagent is 4-(2-Hydroxyethyl)morpholine. 1H-NMR (400 MHz, CD3OD) δ ppm 8.44 (s, 1H), 8.25 (d, J=2.0 Hz, 2H), 7.42 (dd, J=8.4, 1.6 Hz, 2H), 7.41 (d, J=2.0 Hz, 2H), 4.42 (t, J=5.2 Hz, 2H), 3.81 (t, J=4.8 Hz, 4H), 2.87 (t, J=5.2 Hz, 2H), 2.70-2.60 (m, 4H); MS (ESI) m/z 542.1 (M−H)−
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[N:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[N:23]([CH3:29])[C:22]=3[CH:30]=2)[C:14](=[O:31])[CH:13]=1.[H-].[Na+].CC(N(C)C)=O>O>[CH:26]1([C:24]2[N:23]([CH3:29])[C:22]3[CH:30]=[C:18]([N:15]4[CH:16]=[CH:17][C:12]([O:9][CH2:8][C:5]5[S:6][CH:7]=[C:3]([CH:2]([F:10])[F:1])[N:4]=5)=[CH:13][C:14]4=[O:31])[CH:19]=[CH:20][C:21]=3[N:25]=2)[CH2:27][CH2:28]1
Reactant: OCc1nc(C(F)F)cs1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C(F)F)cs4)cc3=O)cc21
Temperature: 120 °C
Yield: 19.7 %

Procedure:
A mixture of (4-(difluoromethyl)-1,3-thiazol-2-yl)methanol (50 mg), 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)-one (69.5 mg), NaH (60% in oil, 12.1 mg) and DMA (1 ml) was heated at 120° C. under microwave irradiation for 2 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (17 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[CH2:17]([Sn](CCCC)(CCCC)C(OCC)=C)[CH2:18]CC.BrN1C(=[O:41])CCC1=O.O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][CH2:9][C:10]([C:11]1[CH:18]=[CH:17][C:6]2[C:5]3[C:4](=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=3)[CH2:13][CH2:8][C:7]=2[CH:12]=1)=[O:41]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2c(c1)CCc1cc(Br)ccc1-2
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc2c(c1)CCc1cc(Br)ccc1-2
Temperature: 85 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
A degassed mixture of 2,7-dibromo-9,10-dihydrophenanthrene (3.5 g, 10.35 mmol), tributyl-(1-ethoxyvinyl)tin (3.8 mL, 11.4 mmol), tetrakis(triphenylphosphine)palladium(0) (598 mg, 0.52 mmol) and dichloro[1,1-bis(diphenyl-phosphino)ferrocene]palladium(II) (378 mg, 0.52 mmol) in 1,4-dioxane (1.0 mL) was heated to 85° C. for 18 hours, cooled to room temperature and N-bromosuccinimide (2.21 g, 12.42 mmol) and water (25 mL) were added. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield 2-bromo-1-(7-bromo-9,10-dihydrophenanthren-2-yl)ethanone (635 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24]C)[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:24])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)N2CC(c3cccc(Cl)c3)OC2=O)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
Twenty grams of [R-(R*,R*)]-5-(3-chlorophenyl)-3-[2-(3,4-dimethyloxyphenyl)-1-methylethyl]-2-oxazolidinone, prepared by the procedure described in U.S. Pat. No. 5.061,727, is dissolved in 100 ml of methylene chloride and cooled to 5° C. under a stream of argon. Ten ml of boron tribromide in 10 ml of methylene chloride is added dropwise over 25 minutes. The reaction mixture is stirred for 20 minutes at 0°-5° C. One hundred and fifty ml of methyl alcohol is added over 40 minutes and the reaction is allowed to warm to room temperature over 1 hour. The solvent is removed by distillation (pot temperature 90° C.) leaving an oil in the bottom of the flask. The reaction flask is charged with 36.9 g of methyl alcohol, cooled to room temperature and 148 g of water is added over 1.5 hours. The reaction is stirred at room temperature for 72 hours, followed by cooling to 5° C. and stirring at this temperature for 1 hour. The resulting precipitate is collected, rinsed with water, and dried to give 17.1 g of the desired product (Yield 92.7% theory).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:19]3[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]3)[CH:8]=2)[NH:3]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([N:19]3[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:21]=[CH:20]3)=[CH:6][CH:5]=2)[C@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:11][C@@H:2]1[CH3:1])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3)cn1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Acetic anhydride (20 mL) was added to ethyl 1-[(cis)-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazole-4-carboxylate (for a preparation see intermediate 83) (3.5 g, 9.06 mmol). The resulting mixture was stirred at room temperature for 24 h then most of the solvent was removed in vacuo. The residue was dissolved in AcOEt (30 mL) and washed repeatedly with a saturated NaHCO3 aqueous solution until the later was basic. The organic phase was then washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in DCM) gave ethyl 1-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazole-4-carboxylate (3.8 g, 8.87 mmol, 98%) as a colourless foam. LCMS (method G): Retention time 0.83 min, [M+H]+=429.11
Reaction SMILES: [Cl:1]C1C=CC(CC=CCCl)=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21](Cl)[CH:22]=[CH2:23])=[CH:16][CH:15]=1.[CH2:25]([N:27]([CH2:35][CH3:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:26].[OH-].[NH4+]>C(#N)C>[Cl-:1].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]/[CH:21]=[CH:22]/[CH2:23][N+:27]([CH2:25][CH3:26])([CH2:35][CH3:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1
Reactant: CCCCCCCN(CC)CC
Reactant: ClCC=CCc1ccc(Cl)cc1
Reactant: C=CC(Cl)Cc1ccc(Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCC[N+](CC)(CC)C/C=C/Cc1ccc(Cl)cc1
Product: [Cl-]
Reaction time: 3 h
Yield: 60 %

Procedure:
Dissolve 35.55 g (0.1768 mole) of a mixture of 1-chloro-4-(4-chloro-2-butenyl)benzene and 1-chloro-4-(2-chloro-3-butenyl)benzene and 27.7 g (0.1607 mole) of N,N-diethyl-1-heptanamine in 220 ml of acetonitrile. Heat the reaction mixture to reflux for 6 hours. Follow the progress of the reaction by thin layer chromatography (acetonitrile: ammonium hydroxide, 95:5). At the completion of the reaction, evaporate solvent and dissolve the residue in 400 ml distilled water. Add solid sodium bicarbonate until pH of solution is 8.5. Wash the aqueous mixture with 4×200 ml petroleum ether and then 5×200 ml Et2O. Add 1N HCl to aqueous layer until pH=1 and then extract with 3×200 ml methylene chloride. Dry over magnesium sulfate, filter and evaporate solvent. Dissolve the material in 150 ml of 2-butanone and then add diethyl ether until solution becomes cloudy. Warm solution until clear and then cool and store in freezer for 3 hours to complete crystallization and then filter title compound. Recrystallize a second time (2-butanone/ether) to provide the title compound in 60% yield.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[NH:7][C:8]3[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:9]=3[N:10]=2)[N:3]=[CH:2]1.[C:16]([N:23]1[CH:27]=[CH:26]N=C1)(N1C=CN=C1)=[O:17].[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)CCN>CN(C)C=O>[F:28][C:29]1[CH:37]=[C:36]([CH2:26][CH2:27][NH:23][C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:9]3[N:10]=[C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)[NH:7][C:8]=3[CH:14]=2)=[O:17])[CH:35]=[CH:31][CH:30]=1
Reactant: NCCc1cccc(F)c1
Reactant: Nc1ccc2nc(-c3cscn3)[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCCc1cccc(F)c1)Nc1ccc2nc(-c3cscn3)[nH]c2c1
Reaction time: 2 h

Procedure:
A solution of 2-thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-5, 100 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL). The 1,1′-carbonyldiimidazole (CDI, 82 mg, 0.51 mmol) was added in one sum to the solution and was stirred for two hours. The 3-fluorophenethylamine (2-1, 72 uL, 0.56 mmol) was added to the reaction mixture via pipet and stirred to completion by LCMS analysis. The LCMS indicated that the dibenzimidazole urea was the by-product. The reaction mixture was partitioned between ethyl acetate and dilute sodium bicarbonate solution. The insoluble urea by-product was removed by vacuum filtration of the layers and the aqueous was extracted (3×10 mL) with ethyl acetate. The organic layer was washed twice with water, once with brine, separated, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting red solid was triturated in ethyl acetate/hexanes mixtures to afford the pure 1-[2-(3-fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea as a gray solid (2-77); 1H NMR (500 MHz, DMSO-d6) δ 12.72 (s, 1H), 9.31 (t, 1H, J=2.0 Hz), 8.52 (s, 1H), 8.34 (d, 1H, J=2.0 Hz), 7.87 (d, 1H, J=1.0 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.35 (d, 1H, J=6.5 Hz), 7.11 (d, 2H, J=8.0 Hz), 7.04 (dt, 1H, J=8.5, 2.0 Hz), 6.96 (dd, 1H, J=8.5, 2.0 Hz), 6.06 (m, 1H), 3.38 (q, 2H, J=7.0 Hz), 2.80 (t, 2H, J=7.0 Hz).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:46]([C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([Cl:39])[CH:41]=3)(=[O:48])=[O:47])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccc(Cl)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Diisopropylethylamine (0.3 mL, 1.7 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 3-Chlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 110 mg, 0.52 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(3-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (97 mg, 56%) as a white solid. MS cald. for C24H24ClFNO4S [(M+H)+]: 476, obsd. 476.4.